The precise mechanisms responsible for the failure of intrahepatic hepatitis C virus (HCV) specific CD8+T cells to control the virus during persistent infection have not been fully defined. We therefore studied the CD8+T-cell response in 27 HLA-A2-positive patients using four previously well-defined HLA-A2-restricted HCV epitopes. The corresponding HCV sequences were determined in several patients and compared with the intrahepatic HCV-specific CD8+T-cell response. The results of the study indicate: (1) intrahepatic HCV-specific CD8+T cells are present in the majority of patients with chronic HCV infection and overlap significantly with the response present in the peripheral blood. (2) A large fraction of intrahepatic HCV-specific CD8+T cells are impaired in their ability to secrete interferon γ(IFN-γ). This dysfunction is specific for HCV-specific CD8+T cells, since intrahepatic Flu-specific CD8 +T cells readily secrete this cytokine. (3) T-cell selection of epitope variants may have occurred in some patients. However, it is not an inevitable consequence of a functional virus-specific CD8+T-cell response, since several patients with IFN-γ-producing CD8+T-cell responses harbored HCV sequences identical or cross-reactive with the prototype sequence. (4) The failure of intrahepatic virus-specific CD8 +T cells to sufficiently control the virus occurs despite the presence of virus-specific CD4+T cells at the site of disease. In conclusion, different mechanisms contribute to the failure of intrahepatic CD8+T cells to eliminate HCV infection, despite their persistence and accumulation in the liver. The precise mechanisms responsible for the failure of intrahepatic hepatitis C virus (HCV) specific CD8 + T cells to control the virus during persistent infection have not been fully defined. We therefore studied the CD8 + T-cell response in 27 HLA-A2-positive Patients using four previously well-defined HLA-A2-restricted HCV epitopes. The corresponding HCV sequences were determined in several patients and compared with the intrahepatic HCV-specific CD8 + T-cell response. (1) intrahepatic HCV-specific CD8 + T cells are present in the majority of patients with chronic HCV infection and overlap significantly with the response present in the peripheral blood. (2) A large fraction of intrahepatic HCV-specific CD8 + T cells are impaired in their ability to secrete interferon γ (IFN-γ). This dysfunction is specific for HCV-specific CD8 + T cells, since intrahepatic Flu-specific CD8 + T cells are readily secrete this cytokine. (3) T-cell selection of epitope variants may hav e occurred in some patients. However, it is not an unsuccessored consequence of a functional virus-specific CD8 + T-cell response, since several patients with IFN-γ-producing CD8 + T-cell responses harbored HCV sequences identical or cross-reactive with the prototype sequence. (4) The failure of intrahepatic virus-specific CD8 + T cells to sufficient control the virus failure despite the presence of virus-specific CD4 + T cells at the site of disease. failure of intrahepatic CD8 + T cells to eliminate HCV infection, despite their persistence and accumulation in the liver.