Cellular immune responses are likely to play a key role in determining the clinical outcome in acute infection with hepatitis C virus (HCV), but the dynamics of such responses and their relationship to viral clearance are poorly understood. In a previous study we have shown highly activated, multispecific cytotoxic T lymphocyte responses arising early and persisting in an individual who subsequently cleared the virus. In this study the HCV‐specific CD8⁺ lymphocytes response has been similarly analyzed, using peptide‐HLA class I tetramers, in a further nine individuals with documented acute HCV infection, six of whom failed to clear the virus. Significant populations of virus‐specific CD8⁺ lymphocytes were detected at the peak of acute hepatic illness (maximally 3.5 % of CD8⁺ lymphocytes). Frequencies were commonly lower than those seen previously and were generally not sustained. Early HCV‐specific CD8⁺ lymphocytes showed an activated phenotype in all patients (CD38⁺ and HLA class II⁺), but this activation was short‐lived. Failure to sustain sufficient numbers of activated virus‐specific CD8⁺ lymphocytes may contribute to persistence of HCV.