Earlier primate studies revealed that oral transmission of immunodeficiency viruses can occur at all ages [R. M. Ruprecht et al., J. Infect. Dis. 179(Suppl. 3):S408-S412, 1999]. Using a stock of pathogenic simian-human immunodeficiency virus, SHIV89.6P, we compared the 50% animal infectious dose needed to achieve systemic infection after oral challenge in newborn and older infant or juvenile rhesus macaques. Unexpectedly, the older monkeys required a 150-fold-lower virus challenge dose than the neonates (P=3.3 x 10(-5)). In addition, at least 60,000 times more virus was needed to achieve systemic infection in neonates by the oral route than by the intravenous route (P <1 x 10(-5)). Thus, route of inoculation and age are important determinants of SHIV89.6P infectivity in rhesus macaques.