Hepatitis C virus infection can be associated with different extrahepatic manifestations, including lichen planus; however, no clear role for HCV in their pathogenesis has been established. T cells were isolated from lichen biopsy specimens of 7 HCV positive patients with oral lichen planus. HCV-specific CD4+ T-cell lines were obtained in 4 patients from lichen lesions but only in 2 of them from the peripheral blood. Different clonal populations were found in oral tissue and peripheral blood of individual patients, as shown by TCR-VP analysis of antigen-specific T cells. Frequency of HCV-specific CD8+ cells tested with 4 different HCV tetramers was significantly higher in the lichen tissue than in the circulation; moreover, lichen-derived HCV-specific CD8+ T cells showed the phenotype of recently activated T cells because most of them were CD69+ and produced interferon gamma (IFN-y) but expanded poorly in vitro upon antigen stimulation. The specificity of HCVreactive T-cell recruitment into the lichen tissue was further confirmed by the absence of HBV-specific T cells within lichen lesions in 3 additional patients with lichen planus associated with HBV infection. Our study shows HCV-specific T-cell responses at the site of the lesions of an HCV-associated dermatologic disease, sustained by HCV-specific T cells with phenotypic and functional characteristics of terminally differentiated effector cells. In conclusion, this finding and the detection of HCV RNA strands in the lichen tissue strongly suggest a role for HCV-specific T-cell responses in the pathogenesis of oral lichen planus associated with HCV infection. (HEPATOLOGY 2002;36:1446-1452.) everal extrahepatic diseases have been reported to be associated with hepatitis C virus (HCV) infection. S However, no clear role for H C V in their pathogenesis has been established, with the exception of mixed cryoglobulinemia for which the interaction between HCV and the CD8 1 molecule has been proposed to play a pathogenetic role.' Among these extrahepatic manifes-