Background: Hepatitis C virus (HCV) infection is associated with a high prevalence of diabetes mellitus (DM). Insulin resistance (IR) is known to play a crucial role in the development of DM in Chronic hepatitis C (CHC) patients. We prospectively investigated the change of insulin sensitivity in CHC patients during 5-year period, and analyzed factors significantly associated with IR. Methods: Subjects consisted of 62 non-cirrhotic CHC patients with normal alanine aminotransferase (ALT) and normal insulin sensitivity (CHC group), and healthy control group of 172 subjects matched by age, sex, body mass index and life styles. We compared initial baseline insulin sensitivity, metabolic parameters and incidence rate of IR at the end of follow up period in both groups. The change of insulin sensitivity and metabolic parameters and development of IR was analyzed, and factors associated with development of IR were evaluated. Results: IR developed in 22.5% of 62 CHC patients and 5.2% of 172 normal individuals (P<0.001). HCV infection per se and genotype 1 were independent risk factors of IR. Initial fasting glucose 90-100 mg/dL, fasting insulin 10 uIU/mL, HOMA-IR 2.3-2.7 were significantly associated with development of IR in CHC group. Conclusions: HCV infection is independent risk factor of IR. Even if CHC patients with normal insulin sensitivity, careful monitoring for IR is necessary.