Our analysis of liver biopsies from HCV/HIV co-infected individuals not only demonstrate that HIV-specific T-cells producing IFN-c and TNF-a are detected in the liver, but also exhibit comparable frequencies of responses to those that are HCV-specific. This observation may explain the added contribution of HIV-specific immune responses to the ongoing intrahepatic damage induced by HCV-specific T-cell responses that are inefficient in clearing the virus. Therapy naïve co-infected individuals demonstrated a higher frequency of intra-hepatic CD8 + T-cells that produce TNF-a in response to both HCV and HIV antigen stimulation compared to HCV mono-infected individuals. In addition, we identified CD8 + T-cells specific for an immunodominant HIV epitope in co-infected liver, demonstrating high frequency of TNF-a expression. Intra-hepatic TNF-a has been previously associated with liver fibrosis, and the accumulation of cells expressing this marker may explain in part the faster rate of liver disease progression found in HCV/HIV coinfection. Further comparisons of TNF-a responses between immunodominant HCV and other HIV epitopes in a larger cohort of individuals are warranted. Contrary to our expectation, viral-specific, intra-hepatic levels of IFN-c were also higher in the therapy-naïve co-infected group, which would be against the expected protective role of IFN-c. However, we interpret this observation as a potential effect of the fibrogenic TNF-a to mask IFN-c protection. On the other hand, viral-specific T-cells are composed of several major populations with unique functional patterns. Therefore, measurement of only one or two T-cell functions may not provide a comprehensive picture of the quality of T-cell responses.