9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a broad-spectrum antiviral agent with potent activity against DNA viruses and retroviruses. We now demonstrate that PMEDAP is highly efficacious when given orally to mice infected with either Moloney murine sarcoma virus (MSV), Friend leukemia virus (FLV), or murine cytomegalovirus (MCMV). PMEDAP markedly delayed MSV-induced tumor initiation when administered orally a t 50, 100, or 250 mg/ kgiday during 5 subsequent days. At the highest dose (250 mg/kg/day), PMEDAP completely prevented tumor formation in the MSV-infected animals. PMEDAP also caused 84-96% inhibition of FLV-induced splenomegaly when given orally to FLV-infected mice at 50-250 mg/kg/day. These PMEDAP treatment regimens were also markedly effective in increasing the survival rate of MCMV-infected mice. lntraperitoneal PMEDAP achieved a comparable antiviral activity at 2-to 5-fold lower doses than oral PMEDAP. However, the therapeutic index (ratio of the toxic dose to the antivirally effective dose) of oral PMEDAP was substantially higher than that of intraperitoneal PMEDAP. Oral PMEDAP at doses of 100, 250, or 500 mg/kg resulted in plasma PMEDAP levels of 0.5-2.5 pgiml, which were sustained for 3 or 6 hours after administration and may account for the high antiviral efficacy achieved.