Significance Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model to explore novel strategies to reduce perinatal human immunodeficiency virus (HIV) infection. Objectives We evaluated the efficacy of pre- and post-inoculation treatment regimens with 9-[2-(phosphonomethoxy)-propyl]adenine (PMPA) to protect newborn macaques against oral and intravenous virus inoculation. Results Untreated newborns became persistently infected following virus inoculation. When three pregnant macaques were given a single subcutaneous dose of PMPA two hours before caesarean section, their newborns became infected following virus inoculation shortly after birth. In contrast, when four newborn macaques were inoculated and started immediately on PMPA treatment for 2 weeks, only one animal became persistently infected; the remaining three PMPA-treated newborns, however, had some evidence of an initial transient SIV infection but were seronegative and healthy at 8 months of age. Our data suggest that PMPA treatment can reduce perinatal HIV infection. Future Directions Future studies can study whether shorter dosage regimens of PMPA can still be effective in preventing SIV infection of newborn macaques. KEYWORDS PMPA, vertical transmission, primate, prophylaxis, prevention, pediatrics