The potential use of variola or another orthopoxvirus such as monkeypox as a weapon of bioterrorism has stimulated efforts to develop new drugs for treatment of smallpox or other poxvirus infections. At the present time only cidofovir is approved for use in the emergency treatment of smallpox outbreaks. Although cidofovir is very active against the orthopoxviruses in vitro and in animal model infections, it is not active when given orally and must be administered with precaution so as to avoid renal toxicity. In an attempt to identify alternative treatment modalities for these infections we have determined the anti-poxvirus activity in vitro of most of the approved antiviral agents as well as a number of cidofovir analogs and prodrugs. From these studies, we have identified the nucleotide analog, adefovir dipivoxil, some alkoxyalkyl esters of cidofovir and a number of prodrugs of cidofovir that warrant further investigation as potential therapies for smallpox or other orthopoxvirus infections.