OBJECTIVE: Significant reductions in perinatal human immunodeficiency virus (HIV) transmission have been demonstrated in which the HIV-infected mothers and their HIV-exposed infants receive prenatal, intrapartum, and neonatal antiretroviral therapy. STUDY DESIGN: We used data that were collected through the Enhanced Perinatal Surveillance system for HIV-exposed singleton births that occurred 1999–2001 in 24 sites. RESULTS: The overall infant infection rate for the 3 years was 4.7%. Compared with zidovudine monotherapy, those patients who received zidovudine with other drugs that included a protease inhibitor and those who received zidovudine and other drugs with no protease inhibitor were less likely to have an infected infant (adjusted odds ratio, 0.4 [95% CI, 0.3–0.07]; adjusted odds ratio, 0.5 [95% CI, 0.3–0.8], respectively). CONCLUSION: These data support the current treatment recommendations and show that infants were less likely to be infected when the mothers were given a prenatal antiretroviral therapy regimen that contained zidovudine with additional antiretroviral drugs with or without a protease inhibitor in addition to receiving antiretrovirals during delivery and neonatally.