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.