In addition to natural epidemics, smallpox has been used as a weapon. Infected bodies or articles of clothing have been used to intentionally spread smallpox through enemy populations. During the French and Indian wars, smallpox-contaminated blankets were given to Native American Indians. About 50% of infected Indians died from the disease.

For decades, many experts have recognized smallpox as a potential weapon. The virus is easily produced and delivered as an aerosol. Today, the virus exists only in a few laboratories around the world. In the early 1970s, about 100 countries agreed to destroy their stores of smallpox and other biological weapons. Despite this, the former Soviet Union developed a large biological warfare program, which included smallpox stores. In 1980, the World Health Organization officially declared that smallpox was eradicated in humans.

Official virus storage sites are located at the Centers for Disease Control and Prevention in Atlanta, GA, and the Institute of Viral Preparations in Moscow, Russia. Viral stores also exist at the Russian State Research Center of Virology and Biotechnology in Koltsovo. The World Health Organization Committee on Orthopoxvirus Infections has recommended destruction of the remaining viral stores, but political factions, including the US government, have delayed this action. Since the fall of the Soviet Union, there is concern that smallpox biological weapon expertise may have migrated to other countries. It is unknown whether stockpiles of smallpox exist in other countries.

As a biological weapon, smallpox could be delivered to large populations as a fine aerosol. Infection results when membranes of the nose or throat come in contact with the virus. Experts believe that only 10-100 virus particles are needed to assure infection and that 1 infected patient will infect about 20 others.