The broad-spectrum antiviral compound 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is currently being evaluated in phase I/II trials in AIDS patients. Long-term clinical application of PMEA is hampered by its low oral bioavailability. The lipophilic ester prodrugs of PMEA bis(pivaloyloxymethyl)-PMEA [bis(POM)-PMEA] and diphenyl-PMEA have been reported to have a favorable oral bioavailability in rats and monkeys. We now determined the antiretroviral efficacy of these prodrugs upon oral administration in SCID (severe combined immune deficiency) mice infected with Moloney murine sarcoma virus (MSV). Compounds were given at a daily dose of 50 or 100 mg of PMEA equivalent per kg, either orally [bis(POM)-PMEA, diphenyl-PMEA, or PMEA], or subcutaneously (PMEA). Oral treatment with bis(POM)-PMEA proved equally effective as subcutaneous PMEA administration, as evidenced by the inhibitory effect on MSV-induced tumor formation and related death of the mice (mean day of tumor initiation: 10.0 days for 100 mg of PMEA equivalent/kg/day, as compared to 4.8 days for untreated control mice). Oral treatment with diphenyl-PMEA or PMEA was much less efficient (mean day of tumor initiation: 7.6 and 6.3 days, respectively). The antiretroviral potency of oral bis(POM)-PMEA was confirmed in Friend leukemia virus (FLV)-infected NMRI mice. The inhibition of FLV-induced splenomegaly upon treatment with oral bis(POM)-PMEA or subcutaneous PMEA was 87% and 80%, respectively (100 mg of PMEA equivalent/kg/day). Oral bis(POM)-PMEA at 250 mg of PMEA equivalent/kg, every other day, displayed moderate activity against murine cytomegalovirus (MCMV) infection in SCID mice, as evidenced by a significant delay in MCMV-induced death. In conclusion, bis(POM)-PMEA should be considered as a useful oral prodrug of PMEA that warrants clinical evaluation in HIV-infected individuals.