The ability of HCV to mutate in response to cytotoxic T lymphocyte (CTL) pressure is increasingly recognized, but the influence of such a mechanism in viral persistence and final disease outcome has not been ascertained. In this study, we performed a detailed longitudinal analysis of cell mediated immunity and HCV evolution in two self limiting and two chronically evolving HCV acutely infected patients, one of whom transiently controlled viremia. Amino acid mutations in immunodominant regions of viruses were observed in all patients, although they conferred viral escape from CTL responses only in chronically infected individuals. Resurgence of viremia coincided with the replacement of the original virus quasispecies with mutant viruses that had escaped recognition by primary CD8(+) T cell responses and infection persisted in the presence of variant viruses which were less efficiently recognized by preexisting and de novo induced T cell responses.