HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus−1, but for HCV the roles of particular alleles and corresponding CD8 + T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses. In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes. Carriage of HLA-B*57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2−3.4), while HLA-B*08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1−0.9]. Two HLA-B*57−restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B*57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B*57−mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B*57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B*57-mediated immune pressure. Our data indicate a role of HLA-B*57−restricted CD8 + T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B*57. The finding that HLA-B*57−mediated antiviral immunity is associated with control of both human immunodeficiency virus−1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.