This study was performed to compare the vigor and phenotype of virus–specific CD4+ and CD8+ T–cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4+ proliferative T–cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV–specific CD8+ T–cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN–γ) staining. Furthermore, although HCV–specific cytolytic CD8+ memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV–infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV–specific memory CD8+ T–cell response. HCV–specific CD8+ T cells displayed a type 1 cytokine profile characterized by production of IFN–γ despite persistent HCV viremia. The paradoxical observation that HCV–specific CD4+ T cells survive and CD8+ T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4+ and CD8+ T–cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8+ effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus.