Smallpox is treated with a combination of antiviral medications and supportive care. Two antiviral drugs are FDA-approved specifically for smallpox, and vaccination within days of exposure can still prevent or lessen the disease. While smallpox was eradicated in 1980, these treatments exist as part of national preparedness in case the virus is ever used as a biological weapon.
FDA-Approved Antiviral Medications
Two antiviral drugs are approved in the United States to treat smallpox: tecovirimat (brand name TPOXX), approved in 2018, and brincidofovir (brand name Tembexa), approved in 2021. Both were approved under the FDA’s Animal Rule, meaning they proved effective in animal studies because testing them on human smallpox cases is not possible or ethical since the disease no longer circulates.
Tecovirimat works by blocking a protein the virus needs to wrap itself inside a protective envelope and spread to other cells. It comes in oral capsules and an intravenous form. The oral version is taken twice daily for 14 days with a meal that contains moderate or high fat, which helps the body absorb the drug. It is approved for adults and children weighing at least about 7 pounds.
Brincidofovir takes a different approach. Once inside a cell, it releases an active compound that interferes with the virus’s ability to copy its own DNA. In animal studies, it provided a significant survival advantage against lethal poxvirus infections and prevented death even when treatment started several days after infection. One major advantage of brincidofovir over an older, related drug called cidofovir is that it does not cause kidney damage, a serious side effect that limited cidofovir’s usefulness. Brincidofovir is also taken by mouth rather than by injection, and it is approved for all ages, including newborns.
Vaccination After Exposure
Getting vaccinated after exposure to the smallpox virus can still make a meaningful difference. According to the CDC, vaccination within 3 days of exposure may prevent the disease entirely. Vaccination within 4 to 7 days likely offers partial protection, meaning you might still get sick but with milder symptoms than an unvaccinated person would experience. Once a rash has already appeared, the vaccine will no longer help.
Two vaccines are FDA-approved for smallpox. ACAM2000 is a second-generation vaccine that contains a live virus capable of replicating in your body. This makes it effective but also means it carries real risks: it can cause heart inflammation, is not safe during pregnancy or breastfeeding, and is contraindicated for people with weakened immune systems, including those with HIV/AIDS, leukemia, or lymphoma. The vaccinia virus in ACAM2000 can also spread from a vaccinated person to close contacts.
JYNNEOS is a third-generation vaccine made from a virus that has been modified so it cannot replicate. This makes it significantly safer. It can be given to people with compromised immune systems, during pregnancy, and to children. It carries no risk of the serious cardiac side effects associated with ACAM2000. For post-exposure use in an emergency, JYNNEOS has no identified contraindications beyond allergy to its ingredients.
Supportive Care
Beyond antivirals and vaccination, much of smallpox treatment is supportive, meaning it focuses on keeping the patient stable and comfortable while the body fights the infection. This includes managing fever, maintaining hydration, and caring for skin lesions to prevent scarring and secondary problems. Antibiotics do not work against the smallpox virus itself, but they are used to treat bacterial infections that can develop when the skin’s protective barrier is broken by the characteristic pox lesions.
Managing Eye Complications
Smallpox can affect the eyes, and this is one of the more serious complications. If the virus reaches the cornea, it can cause scarring that threatens vision. Eye involvement requires evaluation by an ophthalmologist. Treatment typically includes topical antiviral eye drops to fight the infection and topical antibiotics to prevent bacteria from taking hold in damaged tissue.
In severe cases where the cornea develops an ulcer or deeper inflammation, steroid eye drops may be used after the surface of the cornea has healed, to reduce the immune reaction that causes scarring. These are never used without an ophthalmologist’s oversight, and they are always paired with antiviral treatment. Drops that dilate the pupil are also used when the inner eye is inflamed. Topical antivirals are generally continued until all lesions near the eye have fully healed and scabs have fallen off, though one common antiviral eye drop is typically limited to 14 days to avoid irritating the cornea.
How These Treatments Would Be Accessed
Because smallpox no longer exists in nature, these drugs and vaccines are not sitting on pharmacy shelves. They are held in the U.S. Strategic National Stockpile, a federal reserve of medical supplies designed for public health emergencies. In an outbreak, federal and state health authorities would coordinate distribution to hospitals and treatment centers. Healthcare providers would obtain the antivirals and vaccines through established emergency channels managed by the CDC and FDA.
For most people, the practical reality is that smallpox treatment would be delivered through a coordinated public health response rather than something you would seek out on your own. The existence of two effective antivirals, two vaccines that work even after exposure, and clear protocols for supportive care means that the medical toolkit for smallpox, while hopefully never needed, is more robust than it was during the disease’s final years of circulation.