Lichen planus (LP) may represent a mucosal reaction to a variety of factors including hepatitis C virus (HCV) infection. We compared the prevalence of HCV infection in patients with LP of the oral mucosa and chronic liver disease (LP-CLD) with those suffering exclusively from LP or from chronic liver disease (CLD). A total of 267 outpatients participated in a prospective study. There were 41 patients in the LP-CLD group, 128 in the LP group, and 98 in the CLD group. The diagnosis of LP was based on typical macroscopic and histopathologic features and the diagnosis of liver disease on liver histology. Serum samples were screened for anti-HCV antibodies. In 89 patients, serum HCV RNA was also measured. The overall prevalence of anti-HCV antibodies was 29.2% (78/267 patients). Serum HCV RNA levels were positive in 96.2% of anti-HCV-positive patients and in none of anti-HCV-negative subjects. Anti-HCV-positivity was more frequent in the groups of LP-CLD (78%) and CLD (42.8%) than in the LP group (3.1%). It is concluded that HCV infection plays an etiopathogenetic role in CLD associated with oral LP, whereas according to the present findings, the majority of patients suffering exclusively from oral LP are not infected by the HCV.