Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.In July 2018, the Food and Drug Administration approved tecovirimat, the first drug approved for treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.ACAM2000 is a smallpox vaccine developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax. While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells (Vero cells) from an African green monkey. Efficacy and adverse reaction incidence are similar to Dryvax. The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile.In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus.
Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine.In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk, 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described the incident:

On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata–Moscow train in Aralsk. As a result, the epidemic around the country was prevented.