Oral lichen planus (OLP) is a relatively common skin and oral disease that manifests as a mucous reaction to a variety of etiologic factors, including autoimmune disease, drug reaction, diabetes mellitus (DM), hypertension, hepatitis C virus (HCV), urolithiasis, psychogenic factors, and bacterial infection. The purpose of this study was to investigate the relationship between HCV infection and OLP as there is a high prevalence of HCV infection in Taiwan. A total of 1,075 subjects aged at least 15 years participated in the study. The total prevalence of OLP was 3% (32/1,075). OLP was significantly associated with DM (odds ratio, OR, 3.09) and HCV (OR, 2.05). Atrophic-erosive OLP (13/32) and reticular OLP (21/32) were significantly associated with HCV and DM, respectively. Logistic regression analysis showed that elevation of alanine aminotransferase (ALT) significantly increased the risk of atrophic-erosive OLP. We concluded that OLP is significantly associated with HCV and DM in southern Taiwan, particularly in HCV patients with elevated serum ALT levels and atrophic-erosive OLP.