The factors responsible for the low response of chronic hepatitis C patients to interferon-a treatment are not fully understood, although it is known that interferon requires an efficient host immune response to achieve viral clearance. This study was designed to test the hypothesis that hepatitis C virus infection is associated with functional impairment of peripheral blood mononuclear cells, which influence the response to interferon. The proliferative and apoptotic responses of peripheral blood mononuclear cells and purified T cells stimulated with polyclonal mitogenic signals were assessed in 35 chronic hepatitis C patients and 30 healthy controls. Patients were divided into responders and nonresponders according to their sustained response to a course of alpha-interferon-a (3 MU three times weekly for 12 months). The proliferative response to polyclonal mitogens (PHA, TPA) was significantly decreased in nonresponders compared to responders and controls. The defective response was partially normalized by the exogenous addition of interleukin-2 or interleukin-4, and cannot be ascribed to increased apoptosis. Interestingly, the proliferative response of enriched T cells to the same signals was normal. In conclusion, the clinical response to interferon-a defines two different patterns of proliferation by mononuclear cells in chronic hepatitis C patients. This suggests that an alteration of the immune system in these patients may underlie their inadequate response to antiviral therapy.