CD8+ T cells represent a sizable component of the liver inflammatory infiltrate in chronic hepatitis C and are thought to contribute to immune-mediated tissue injury. Because chronic stimulation may promote the expression by CD8+ T cells of distinct human leukocyte antigen class I–specific natural killer cell receptors (NKRs) susceptible to both inhibiting effector functions and promoting cell survival, we examined the distribution and characteristics of CD8+ T cells with such receptors in chronic hepatitis C patients. NKR CD8+ T cells were detectable in liver and peripheral blood from hepatitis C virus (HCV)–infected patients but were not major subsets. However, the frequency of NKG2A+ CD8+ in the liver and in a lesser extent in the peripheral blood was positively correlated to histological activity in HCV-infected patients. No such correlation was found with KIR+ T cells in liver in HCV-infected patients and with the both NKR CD8+ T cells in hepatitis B virus (HBV) infected patients. Circulating CD8+ T cells expressing KIRs exhibited phenotypic features of memory T cells with exacerbated expression of the senescence marker CD57 in patients. NKG2A+CD8+ T cells were committed T cells that appeared less differentiated than KIR+CD8+ T cells. In HCV-infected patients, their content in perforin was low and similar to that observed in NKG2ACD8+ T cells; this scenario was not observed in healthy subjects and HBV-infected patients. Both NKG2A and KIRs could inhibit the response of HCV-specific CD8+ T cells ex vivo. Conclusion: These results support the concept that an accumulation in the liver parenchyma of NKR+CD8+ T cells that have functional alterations could be responsible for liver lesions. They provide novel insights into the complexity of liver-infiltrating CD8+ T cells in chronic hepatitis C and reveal that distinct subsets of antigen-experienced CD8+ T cells are differentially sensitive to the pervasive influence of HCV (HEPATOLOGY 2007.)