Smallpox: Symptoms, Spread, and Treatment

Medically Reviewed by Jabeen Begum, MD on January 31, 2024
11 min read

Smallpox is a serious infectious disease caused by a virus that’s no longer found in nature. It was passed from person to person. People with smallpox had flu-like symptoms and a rash that would spread across their bodies.

Smallpox was deadly. About 30% of people who got smallpox died. In the 1900s, before smallpox was eradicated in 1980, it killed about 300-500 million people around the world. The World Health Organization (WHO) called smallpox “one of the most devastating diseases known to humanity.”

Smallpox history

Historians believe that smallpox has been around for at least 3,000 years. This is based on smallpox-like rashes found on Egyptian mummies from the 18th and 20th Egyptian dynasties. Historians say that the growth of civilization and exploration, as well as expanding trade routes, caused the disease to spread to other countries and continents.

People began to notice that those who got smallpox and survived never got it again. They realized that the best way to prevent getting sick was to expose yourself to the virus. This was often done by inhaling or rubbing the material from a smallpox sore onto the skin. Eventually, English doctor Edward Jenner learned that exposing people to the similar but less deadly cowpox virus helped protect them from smallpox.

Sometime in the 1800s, the smallpox vaccine was modified to use a poxvirus that was similar to smallpox but less harmful. However, the disease continued to infect people around the world. The last smallpox outbreak in the U.S. happened in 1949.

In 1967, WHO launched a plan to wipe out smallpox around the world through widespread immunization and surveillance. As a result, no cases of smallpox have happened since 1977. WHO declared it eradicated in 1980.

Today, scientists keep only a small amount of the virus alive under tightly controlled conditions in the U.S. and Russia for medical research.

Routine smallpox vaccinations stopped in the U.S. and in many other countries in 1972, and in all other WHO member countries by 1986. Many adults living today likely got the vaccine as children.

Smallpox gets its name from the most common sign of the disease: small skin-colored blisters that pop up on the face, arms, and body, and fill up with pus.

Other symptoms include:

Smallpox incubation period

Usually, you won’t show symptoms of smallpox for about 10-12 days after you've been exposed to someone infected with the virus. But the incubation period (the number of days it takes for symptoms to appear after you’re infected with the virus) can be as little as 7 days or as long as 17 days.

The virus enters the body through the membranes in your mouth, nose, or eyes. After about 3-4 days, it travels to your lymph nodes and into your bloodstream where it multiplies. During this time, you won’t show symptoms.

About 8 days after exposure, the virus begins to spread to the small blood vessels of the skin and back to the membranes of the mouth. At this point, you may begin to feel like you’re getting sick but not show symptoms.

Early smallpox symptoms

The earliest symptoms happen about 12 days after exposure. You may get a high fever, feel extremely weak, vomit, and have body aches. About 2 days after that, the virus begins to spread to the outer layer of your skin. Once you get a fever, you become contagious and can spread the disease to other people.

Around 12-14 days after exposure, you’ll develop a flat red rash that begins in the membranes of the mouth and throat and on your face and hands. It then spreads to the rest of the body, usually within 24 hours. The rash develops blisters within a day or two. Once the rash appears, your fever will probably drop, and you’ll begin feeling better.

What does smallpox look like?

Smallpox blisters usually cover a person’s entire body from head to toe, including the mouth and throat. Here is how the rash changes throughout the illness:

  • The rash starts with flat red sores in the mouth and quickly spreads across the body within about 24 hours.
  • The rash turns into raised bumps filled with clear liquid.
  • The bumps turn into pus-filled blisters a day or two later.
  • The blisters crust over, usually about a week later.
  • Scabs form over the blisters and then fall off over the next 3-4 weeks. They can cause permanent scars.

Smallpox vs. chickenpox

Smallpox and chickenpox are both caused by viruses. Both cause blisters to form on the skin. But there are distinct differences:

  • Smallpox and chickenpox are caused by different viruses. The variola virus causes smallpox, while the varicella virus causes chickenpox.
  • Chickenpox is usually mild, while smallpox was more serious, killing about 30% of the people it infected.
  • Chickenpox sores usually show up first on the trunk of the body or the face. Sores are rarely seen on the palms or soles of the feet. Smallpox sores usually appear first in the mouth, throat, face, or forearms before spreading over most of the body. Most people with smallpox have sores on their palms or the soles of their feet.

The variola virus causes smallpox. There are two forms of the virus. The more dangerous form, variola major, led to a form of smallpox that killed about 30% of people who were infected. Variola minor caused a less deadly type that killed about 1% of those who got it.

Two forms of smallpox -- hemorrhagic and malignant -- were more deadly than the common strain.

Hemorrhagic smallpox tended to affect adults, including pregnant adults, not children. Those infected with this strain had more serious symptoms, including fever, pain, and headaches, and they leaked blood from their blisters and mucous membranes. People usually died of blood poisoning within a week.

Malignant smallpox tended to affect children. Instead of raised blisters, infected individuals developed flat lesions that emerged on the skin surface. Most people who got this form of smallpox also died of blood poisoning.

Smallpox is spread from person to person. But you're only contagious once you develop a fever. After that, you are most contagious in the first 7-10 days. This is because the virus is most numerous in your saliva. Once scabs form on your blisters, you can still spread the disease but you're less contagious. You're considered noncontagious when the last scab falls off.

The disease enters your body through the mucous membranes in your mouth, nose, or eyes. You could get it:

  • By breathing in the virus during close, face-to-face contact with an infected person. It usually spreads through drops of saliva when the person coughs, sneezes, or speaks.
  • By handling the clothes or sheets of an infected person or coming into contact with their body fluids.
  • Very rarely, smallpox has spread among people in small, enclosed spaces, probably through air in the ventilation system. Animals and insects don’t spread the disease.
  • If the virus were spread through an act of terrorism. This is a rare possibility, but in case it happens, governments around the world have stockpiled smallpox vaccines to prevent the spread.

Because smallpox hasn’t been diagnosed in decades, it’s likely that doctors wouldn’t recognize the disease in a patient right away. It’s possible to diagnose the condition by testing a sample of tissue taken from a smallpox blister. A single diagnosis would be considered a worldwide health emergency.

In the event a case does emerge, there are two antiviral drugs approved by the U.S. FDA to treat the disease: tecovirimat (TPOXX) and brincidofovir (Tembexa). Both have been shown to stop the growth of the virus that causes smallpox.

The drug cidofovir has been shown to stop the growth of the smallpox virus.It’s not FDA-approved to treat smallpox, but it could be used during an outbreak under certain circumstances, such as an Emergency Use Authorization.

None of these drugs have been tested in people sick with smallpox. But tecovirimat and cidofovir have been shown to work in animals with diseases similar to smallpox, and it’s believed that brincidofovir would, too.

Tecovirimat and cidofovir are stockpiled within the U.S. Strategic National Stockpile, which holds medications and medical supplies to protect the American public in the event of a public health emergency, such as a smallpox outbreak.

Getting the vaccine within 3-4 days of contact with the virus may make the disease less severe or may help prevent it.

Beyond that, medical care aims to ease symptoms (such as fever and body aches) and control any other illnesses that a person can get when their immune system is weak. Antibiotics can help if someone gets a bacterial infection while they have smallpox.

If people get hemorrhagic or malignant smallpox, they are more likely to die. The more fatal forms of the disease are more likely to affect those who are pregnant or immunocompromised.

People who survive smallpox may have scarring on their face and body. In rare cases, they may become blind. Smallpox can also cause infertility in men and those assigned male at birth (AMAB), and it may cause miscarriage or stillbirths in those who are pregnant.

Scientists use the vaccinia virus, which is the cousin virus to variola, to make the smallpox vaccine, because it poses fewer health risks. The vaccine helps the body's immune system to make antibodies, which recognize and protect against the variola virus and help prevent smallpox disease.

Routine smallpox vaccinations stopped in 1972 in countries where cases were no longer reported, including the U.S. Other WHO member countries stopped routine smallpox vaccinations in 1986.

No one knows for sure how long the smallpox vaccine protects people from the disease. Some experts believe it lasts up to 5 years and wears off over time. Since it may not give lifelong protection, anyone vaccinated years ago as a child could be at risk of future infection by the variola virus. The only people known to be immune for life are those who have had smallpox and survived.

WHO and its member countries keep an emergency stockpile of the smallpox vaccine. It’s rarely used today, except for those few people who are around the variola virus, such as laboratory researchers working with variola or similar viruses.

Who invented the smallpox vaccine?

English doctor Edward Jenner developed the first successful smallpox in 1796. He had noticed that milkmaids who had gotten sick with cowpox seemed immune to smallpox. He assumed that exposure to the cowpox virus must help protect against smallpox. He tested the theory on the 9-year-old son of his gardener, later exposing the boy to smallpox, but the boy never got sick.

Jenner’s smallpox vaccine became commonly widely accepted. At some point in the 1800s, the cowpox virus in the vaccine was replaced with the vaccinia virus.

Smallpox vaccine scar

Many people (mostly in their 40s or older) who got the smallpox vaccine have a permanent scar on their arm where they got the injection. This scar isn’t from the needle but rather from the body’s immune reaction to defend itself against the controlled infection caused by the live vaccinia virus in the vaccine. Exposure to the virus usually left a sore and itchy bump at the injection site. The bump turned into a larger blister that eventually fell off and left a scar.

The formation of a sore bump — and ultimately, a scar — at the injection site lets you know that the immunization process was successful.

Smallpox vaccine risks

Smallpox vaccine side effects are generally mild, such as:

  • Soreness in the arm that received the injection
  • Itching
  • Swollen lymph nodes
  • Fever
  • Headache
  • Body aches
  • Mild rash
  • Fatigue

Some side effects can be dangerous, especially for people with weakened immune systems. They can range from skin reactions to a serious nervous system condition called encephalitis, which can lead to convulsions, coma, and death. But these side effects are very rare. Based on historical data, for every 1 million people vaccinated for smallpox, only one to two people died from a bad reaction.

People who would have a higher risk of a reaction to the vaccine include:

  • Those who are pregnant or breastfeeding
  • People with skin disorders such as eczema
  • People with a weak immune system due to a medical condition such as leukemia or HIV
  • People on medical treatments, such as for cancer, that make the immune system weak
  • People who have had a serious allergic reaction to a previous smallpox vaccine

It’s hard to know how major a threat a smallpox outbreak would be today. Scientists can’t be sure because: 

  • The number of people around the world with weakened immune systems is higher today than when smallpox existed.
  • Countries used vaccines of different strengths during the global effort to end smallpox.
  • There’s no way to know for sure how long these different vaccinations give immunity to the virus.

If an outbreak of smallpox were to happen today, public health measures would likely include these steps:

  • Finding and vaccinating infected people
  • Vaccinating health care workers and others at risk of infection
  • Isolating smallpox patients to keep them from spreading the disease
  • Providing vaccinations for the public, as needed, to contain the outbreak

Smallpox was eradicated in 1980, and no cases have happened since 1977. Scientists keep a small amount of the smallpox virus alive under tightly controlled conditions in the U.S. and Russia for medical research. In the event of another smallpox outbreak, governments around the world have smallpox treatments and vaccines stockpiled to protect the public.

Does smallpox still exist?

Smallpox has been eliminated worldwide. But researchers keep a small amount of the live virus in tightly controlled conditions for research purposes.

Is monkeypox the same as smallpox?

Mpox is caused by the monkeypox virus, which is part of the same family of viruses as the smallpox virus. The symptoms of mpox are similar to but milder than smallpox and the disease is nowhere near as deadly. Neither mpox nor smallpox are related to chickenpox.

Why was smallpox so fatal?

Smallpox was so deadly because there were no reliable treatments available. And while the first vaccine was developed in 1796 and was widely accepted, it was not widely administered. Smallpox killed as many as 300-500 million people in the 1900s. Thanks to global immunization efforts, the disease was wiped out by 1980.