It is unknown whether diabetes mellitus is a risk factor of the hepatocarcinogenesis in patients with chronic hepatitis C. Three hundred eleven anti-hepatitis C virus (HCV) -positive patients who had undergone liver biopsies were studied. Patients with histologically proven cirrhosis or withdrawing within 12 months were excluded. Thus, the remaining 279 patients were followed-up for 65.9 +/- 29.4 months until the occurrence of hepatocellular carcinoma (HCC). During the observation period, HCC developed in 13 patients. Diabetes, age, sex, habitual alcohol intake, history of blood transfusion, serum alpha-fetoprotein level, histological findings, HCV genotype, viral load, and interferon therapy were assessed as potential risk factors. The Cox proportional hazard model identified that diabetes mellitus, histological staging, and age were independently associated with the occurrence of HCC. With multivariate analysis, only diabetes mellitus and age were associated with the occurrence of HCC. Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C.