Persons with human immunodeficiency virus (HIV) and hepatits C virus (HCV) coinfection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV-specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. We examined intrahepatic cellular immune responses to HCV antigens to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4-enriched, liver-infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin (IL) 10 was determined using enzyme-linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN-γ or TNF-α in response to HCV or recall antigens. However, there was a significant increase in IL-10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinfection. In conclusion, subjects with coinfection have an alteration of intrahepatic HCV-specific IL-10 cytokine response that may have implications for HCV-related disease progression. (Hepatology 2004;40:125-132.)