The CD4+ T cell response is of critical importance in determining the fate of many viral infections. Clearance of HCV has a strong association with the MHC class II antigen HLA-DR11 suggesting a key role for CD4+ T cells. We used an epitope-prediction program to identify multiple novel HLA-DR11-restricted epitopes derived from several HCV proteins. These epitopes then allowed us to explore the qualitative and quantitative aspects of specific CD4+ T cell responses in HLA-DR11+ patients. Irrespective of the time since viral clearance, all the non-viremic patients recognized four epitopes with a high frequency of IFN-gamma-producing memory CD4+ T cells. There appeared to be two subpopulations of memory cells, immediate "effector" memory cells (Th1 phenotype) and resting "central" memory cells (Th1/0). Chronically infected patients revealed an almost complete absence of HCV epitope-specific IFN-gamma-producing T cells. However, three of these epitopes induced IL-10 production (down-regulatory) raising the question as to whether these cells play a role in viral persistence. The frequency and phenotype of memory cells is likely to reflect the magnitude of the initial immune response, and suggests that a high frequency of IFN-gamma-secreting CD4+ T cells to multiple epitopes are important in clearance of HCV.