Background: To assess the role played by the immune response in the outcome of hepatitis C virus infection, the CD4⁺ T-lymphocyte response to viral antigens was studied in infected individuals with different clinical courses. Methods: Using six recombinant proteins of hepatitis C virus, the study assessed the proliferative responses of peripheral blood mononuclear cells from 41 patients with chronic hepatitis C, 11 patients whose chronic hepatitis was successfully treated with interferon alfa and 11 healthy HCV seropositive individuals. Results: (1) Sixty-five percent of hepatitis C virus-seropositive individuals had CD4⁺ T-cell responses to viral proteins. (2) All viral proteins were immunogenic for T cells, although NS4 was the most immunogenic. (3) There was a significant correlation between the presence of CD4⁺ T cell responses to Core and a benign course of infection in healthy seropositives, most of whom were viremic. Conclusions: CD4⁺ T-cell responses to Core, although they do not coincide with virus clearance, are associated with a benign course of infection and may be required to maintain humoral and cellular responses protective against the disease.