BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes.AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR.METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR).RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006).CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.