BACKGROUND/AIMS: Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS: Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS: The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8 microU/ml vs. 22.2+/-4.9; P = 0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P = 0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P = 0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P < 0.001) and fibrosis stage (P < 0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of < 2 were 6.5 times more likely to achieve SVR than those with HOMA-IR > or = 2. CONCLUSIONS: Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.