The smallpox vaccine is the only effective preventive treatment for the deadly smallpox disease.

In 1977, smallpox, long considered to be the most deadly and persistent human pathogenic disease, was eradicated by the World Health Organization through a massive vaccination program. However, the variola virus that led to the death of 300 million in the 20th century alone was not completely exterminated with the disease it caused. Two known repositories of the virus were left for possible anti-bio-weaponry research; one stockpile at the Centers for Disease Control in Atlanta, Georgia and another in the State Research Center of Virology and Biotechnology in Koltsovo, Russia.

The vaccine that eventually eradicated smallpox, developed by Edward Jenner in 1796, consists of the virus which causes the related, yet far milder, cowpox disease; this virus is appropriately named vaccinia, from the Latin 'vaca' which means cow. This vaccine has functional virus in it which improves its effectiveness but, unfortunately, causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients, and people with eczema) and is not yet considered safe for pregnant women. A small, yet significant, percentage of healthy individuals also suffer adverse side-effects which, in rare cases, include permanent neurological damage. Vaccines that only contain attenuated ("killed") vaccinia virus have been proposed but some researchers have questioned the possible effectiveness of such a vaccine. Others point out that mass vaccinations would probably not be needed to counter a bioterrorist attack if many millions of doses of the current (possibly improved) vaccine could be delivered to victims within several days of exposure (the vaccine is effective to that point). This, along with vaccinations of so-called first-responders, is the current plan of action being devised by the US Department of Homeland Defense and FEMA in the United States (the DHD was formed as a result of the September 11, 2001 terrorist attack).

The vaccine can cause complications for those around those who are vaccinated. People who get the vaccine will shed virus particles through vesicles on their skin and possibly through their respiratory tract. Infections in close and not-so-close contacts can ensue. The current plan to vaccinate first responders has the potential to cause infection in the most vulnerable section of the population, the hospitalized ill. Family contacts are also susceptible, although they are less vulnerable because their immune systems are presumably intact. Secondary infection can cause skin disease, pulmonary disease and rarely, neurologic disease.

As of June 21, 2003, a scientific advisory panel had issued a recommendation against further vaccination of first responders because a significant number of those vaccinated suffered heart problems, notably pericarditis and myocarditis.

The main problem with developing a new, supposedly safer vaccine, is that, barring a bioterrorist attack on immunized individuals, its effectiveness cannot be tested on humans, and other animals do not naturally contract smallpox. Monkeys at USAMIID research facilities have been infected, but tests on animals that are artificially infected with a human disease are notorious for giving false or misleading results. To demonstrate safety and effectiveness, human trials always have to confirm data obtained from animal testing.

The smallpox vaccine is also the only known treatment for monkeypox. As with smallpox, vaccination after infection is effective if the vaccine is given before symptoms develop.

See also: Balmis Expedition