We investigated the proliferative response and IL-2 receptor (IL-2R) expression in peripheral blood mononuclear cells (PBMC) activated with anti-CD3 mAb alone or in combination with anti-CD28 mAb in a group of hepatitis C virus (HCV)-infected patients with detectable viremia demonstrated by "nested" PCR. PBMC from HCV patients and controls showed similar proliferative responses either to anti-CD3 mAb, 64.1, and/or to anti-CD28 mAb, 9.3. No differences were found in anti-CD3 or anti-CD3 plus anti-CD28-induced proliferative responses between patients who demonstrated circulating PBMC bearing HCV-RNA when compared to those with negative HCV-RNA PBMC. Moreover, flow cytometry studies confirmed that anti-CD3 alone or in combination with anti-CD28 were able to induce a significant increase of IL-2R expression in patients or controls PBMC. Both groups showed similar basal CD28 expression. These results indicate that both CD3- and CD28-activating pathways are preserved in HCV-infected patients with chronic active liver disease.