A major safety concern of using live-attenuated vaccine strategies against AIDS is the potential exposure of neonates or fetuses to vaccine virus from the mother. Here we report that high viral loads and disease were observed in only 2 of 18 neonatal monkeys infected with gene-deleted vaccine strains of simian immunodeficiency virus. Pathogenicity was restricted to neonates born to unvaccinated mothers, that is, lacking maternal immunity, and that received extremely high doses of vaccine virus orally. No in utero transmission of vaccine virus was observed in four neonates born to mothers vaccinated during the second trimester. Our results suggest that the live attenuated vaccine approach should remain a viable option for preventing HIV infection and disease in high-risk human populations.