Both strong antigenic avidity and acquisition of proper effector functions contribute to the efficacy of antiviral T cell responses. To correlate these parameters with the outcome of hepatitis C virus (HCV) infection, we characterized HCV‐specific CD8 T cell lines isolated after immunomagnetic sorting of peripheral blood mononuclear cells from human leukocyte antigen A*02 (HLA‐A*02) individuals with various HCV serological statuses, using recombinant HLA‐A*0201 multimers loaded with three immunodominant HCV genotype 1‐derived epitopes. CD8 T cells specific for these three epitopes were derived from most HLA‐A*0201 individuals, regardless of their HCV serology or clinical outcome. Donors recovered from genotype 1 HCV infection were enriched for high‐avidity T cells with enhanced interferon gamma (IFN‐γ), tumor necrosis factor alpha, and cytotoxic T lymphocyte responses, when compared with seronegative donors and seropositive patients infected with irrelevant HCV genotypes. Patients chronically infected with genotype 1 strain yielded almost exclusively low‐avidity T cells, whose hyporesponsiveness was primarily attributable to low T cell receptor (TCR) avidity rather than intrinsic functional defects. Conclusion: This study suggests that strong IFN‐γ responses associated with efficient viral clearance primarily result from Ag‐driven selection/survival of HCV‐specific T cells expressing high‐avidity TCR. It also suggests a link between the quality of the initial HCV‐specific T cell repertoire and susceptibility to chronic infection. (HEPATOLOGY 2008.)