To assess the aetiology of liver disease associated with lichen planus, we prospectively studied 70 consecutive newly diagnosed patients with oral lichen planus (OLP) living in northwest Italy (Piemonte) and 70 controls matched for age and sex with other oral keratoses coming from the same district. Twenty-two patients with OLP (31.4%) and 9 controls (12.9%) were found to be affected by chronic liver disease (CLD) (P = 0.014). In sixteen of the 22 OLP patients with CLD the liver disease was hepatitis C virus (HCV)-related, whereas 2 of the 9 controls had a HCV-related CLD (P = 0.016). In another OLP case, liver damage was related to a combination of HCV and alcohol abuse. The prevalence of HCV antibodies in the whole OLP group (27.1%) was significantly higher than in controls (4.3%) (P = 0.014), whereas no difference was found between the OLP and control groups regarding hepatitis B virus markers and other common causes of CLD. HCV infection was more frequently found in patients with erosive OLP (58.8%) than in patients with non-erosive OLP (13.2%) (P = 0.004). Serum HCV-RNA was detected by polymerase chain reaction (RT-PCR) in the majority (93.7%) of OLP patients who had HCV antibodies. Excluding OLP and control patients with HCV markers, there was no difference between the two groups regarding frequency of CLD. Our data show that HCV is probably the main pathogenic factor in liver disease of Italian patients with OLP, and suggests that HCV could be involved in the pathogenesis of OLP.