OBJECTIVE To determine whether cytotoxic T lymphocytes have a beneficial effect during infection with the simian immunodeficiency virus (SIV) in macaques. METHODS We followed up 12 rhesus macaques experimentally infected with SIV. Cytotoxic T lymphocytes were detected in nine macaques, who were subdivided into a group of high responders (n = 6), with a sustained and polymorphic response directed against most SIV proteins, and a second group of weak responders (n = 3), in which the responses were only transient and directed against only a few proteins. A third group was characterized by the absence of any cytotoxic T-lymphocyte response (n = 3). Proliferative responses closely paralleled cytotoxic responses in intensity and evolution. RESULTS Clinical profiles and CD4 cell counts were markedly linked to cytotoxic activity; five out of six macaques that responded to multiple proteins were still healthy 2 years after SIV infection, with two of them presenting a decrease in circulating CD4 cells concomitant with the disappearance of the cytotoxic T-lymphocyte response. Conversely, five non-responder or weak-responder macaques developed overt disease after 4-21 months. CONCLUSIONS These data suggest that a cytotoxic response may predict a better clinical outcome.