Mice infected intravenously with vaccinia virus develop characteristic lesions over the entire tail surface. This experimental virus infection presents a highly sensitive and reliable model for evaluating the antivaccinia activity of antiviral compounds. Ara-C (1-beta-D-arabinofuranosylcytosine), ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), IUdR (5-iodo-2'-deoxyuridine) as well as two novel analogs of IUdR, EtUdR (5-ethyl-2'-deoxyuridine), and NCSUdR (5-thiocyanato-2'-deoxyuridine), were found to inhibit the formation of vaccinia tail lesions, when administered intraperitoneally once daily for 7 days starting immediately after virus infection. The order of (decreasing) activity was: ara-C greater than IUdR greater than NCSUdR greater than ribavirin greater than EtUdR. Various drug combinations, involving IUdR + ara-C, NCSUdR + ara-C, NCSUdR + IUdR, NSCUdR + ribavirin, etc., were evaluated but none proved more efficacious than either compound administered alone.