To assess the possible role of cytotoxic T lymphocytes (CTLs) in containing the spread of human immunodeficiency virus in acutely infected individuals, the temporal evolution of the virus-specific CD8+ lymphocyte response was defined in simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys. A brief period of SIVmac plasma antigenemia was seen 9 to 16 days following intravenous infection with SIVmac, ending as the absolute number of CD8+ peripheral blood lymphocytes (PBLs) increased. In a prospective assessment of the ability of CD8+ lymphocytes of these monkeys to suppress SIVmac replication in autologous PBLs, inhibitory activity was detected as early as 4 days, with a more pronounced effect 12 to 16 days following infection. SIVmac Gag- and Nef-specific CD8+ effector cell activities were demonstrable in PBLs of animals by 2 weeks following virus inoculation. In fact, SIVmac-specific CTL precursors were documented in the PBLs of rhesus monkeys 4 to 6 days after SIVmac infection. These studies indicate that AIDS virus-specific CD8+ CTLs are present in PBLs within days of infection and may play an important role in containing the early spread of virus.