Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a practical animal model of pediatric AIDS. Intravenous inoculation of rhesus newborns with uncloned SIVmac resulted in a high virus load, no antiviral immune responses, severe immunodeficiency, and a high mortality rate within 3 months. In contrast, immediate oral zidovudine (AZT) treatment of SIV-inoculated rhesus newborns either prevented infection or resulted in reduced virus load, enhanced antiviral immune responses, a low frequency of AZT-resistant virus isolates, and delayed disease progression with negligible toxicity. These results suggest that early chronic AZT treatment of human immunodeficiency virus-exposed newborns may have benefits that outweigh its potential side effects.