Hepatitis C virus (HCV) infection induces a variety of extrahepatic manifestations such as oral lichen planus (OLP). To clarify the role of HCV in the development of OLP, we investigated the occurrence of OLP in patients with chronic hepatitis C treated with interferon (IFN). Of 275 patients with chronic hepatitis C, 6 developed OLP during the IFN treatment. However, OLP developed in none of 230 patients with chronic hepatitis C who did not undergo the IFN therapy. The IFN treatment in chronic hepatitis C patients developed OLP significantly, as compared with the non-treated group (p < 0.05). 4 of 6 patients who developed OLP during the IFN treatment had a complete response with normalization of ALT levels and undetectable HCV RNA after the treatment. There were no significant correlations between the effect of the IFN treatment and outcome of OLP. Furthermore, 3 of the 6 patients developed OLP, when serum HCV RNA became negative. These results suggest that direct viral factors may not be important in the pathogenesis of OLP in patients with chronic hepatitis C. Immunological changes caused by IFN may play a role in the development of OLP associated with HCV infection.