Hepatitis C virus (HCV) is yet another example of a pathogen that persists in the presence of a readily apparent immune response. As evidence for both humoral and cellular immune responsiveness is quite strong, our studies have begun to examine whether qualitative defects in CD4 T-cell responses to viral antigens may help to explain why HCV is not eliminated in the vast majority of infections. Direct evidence that CD4 T cells play a role in HCV persistence is lacking, but several observations are consistent with this possibility. Importantly, it does not exclude the role of antibody or killer T cells in the immunopathogenesis of HCV infection. In addition, we discuss the consequences of viral mutation and how naturally occurring variants in immunodominant viral epitopes can effectively suppress helper T-cell responses to wild type virus.