The antiviral efficacy of phosphonoacetic acid (PAA) was studied in localized skin lesions of rabbits produced by the intradermal inoculation of vaccinia virus (VV) and of Shope fibroma virus (SFV). Systemic administration of PAA by intraperitoneal injections had no significant effect on the pustular lesions induced by VV or on the benign skin tumors caused by SFV. A complete suppression of the appearance of VV-induced pustular lesions was achieved by 2% PAA ointment applied twice daily for 4 days, starting 24 hr after virus inoculation. A significant effect against SFV-induced tumors was obtained by PAA ointment applied beginning either 24 or 72 hr after virus inoculation. A complete suppression of SFV-induced tumors was observed when a dose of 10 mg PAA was injected intralesionally once daily for 5 days, beginning treatment 24 hr after virus inoculation. A significant reduction of the intensity of the tumors was seen following the same treatment schedule but with a delay of 72 hr after virus inoculation or by reducing the length of treatment to 3 days or with a dose of 1 mg injected intradermally daily for 5 days. After the healing of the lesions, PAA-treated rabbits were resistant to reinfections to the same extent as those in which spontaneous healing had occurred.