Hepatitis-C virus (HCV) infection induces an acute and chronic liver inflammation through an immune mediated pathway that may lead to cirrhosis and liver failure. Indeed, HCV-related hepatitis is characterized by a dramatic lymphocyte infiltrate in the liver which is mainly composed by HCV non-specific cells. Several data indicated that IFN-gamma secretion by intrahepatic lymphocytes (IHL) may drive non specific cell homing to the liver inducing IP-10 production. An interesting hallmark of these IHL is the recruitment of lymphocytes associated with mechanism of innate immunity such as NK, NKT and gamma delta T lymphocytes. CD81 triggering on NK cell surface by the HCV envelope glycoprotein E2 was recently shown to inhibit NK cell function in the liver of HCV-infected persons resulting in a possible mechanism contributing to the lack of virus clearance and to the establishment of chronic infection. In contrast, intrahepatic NKT cells restricted to Cd1d molecules expressed on the hepatocyte surface may contribute to a large extent to the liver damage. Finally, an increased frequency of T cell expressing the gamma delta TCR was observed in HCV-infected liver and recent observations indicate that intrahepatic gamma delta T cell activation could be directly induced by the HCV/E2 particle through CD81 triggering. These cells are not HCV specific, are able to kill target cells including primary hepatocytes and their ability to produce Th1 cytokines is associated with an higher degree of liver disease. Altogether, CD1d/NKT and/or E2/CD81 interactions may play a major role in the establishment of HCV immunopathogenesis. In absence of virus clearance, the chemokine-driven recruitment of lymphocytes with an innate cytotoxic behavior in the liver of HCV infected patients may boost itself leading to the necroinflammatory and fibrotic liver disease.