AIM: To elucidate the role of insulin resistance (IR) and serum adiponectin level in hepatocellular carcinoma (HCC) associated with chronic hepatitis C. METHODS: Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC. Homeostasis model assessment of IR (HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus (HCV) infection. RESULTS: Among HCC patients, type 2 diabetics (DM) was more prevalent in HCV subjects (35.6%, n = 59) compared to hepatitis B virus (HBV; 12.7%, n = 63) or non-HBV, non-HCV cases (7.1%, n = 28). In patients with chronic hepatitis C, HCC subjects had higher blood sugar ( P < 0.001), insulin level ( P = 0.003) and HOMAIR ( P = 0.018) than those with chronic hepatitis and advanced fibrosis. Age, male sex and body mass index were significantly associated with serum adiponectin level, whereas HOMA-IR was not. Based on stepwise logistic regression analysis, age (OR: 1.124, P < 0.001), serum insulin level (OR: 1.585, P < 0.001), HOMA-IR (OR: 0.495, P = 0.001), DM (OR: 11.601, P = 0.002) and male sex (OR: 3.877, P = 0.016) were independently associated with HCC. This result was similar even if the diabetic subjects were excluded for analysis. CONCLUSION: Insulin resistance measured by HOMAIR, regardless of the presence of diabetes, is signifi- cantly associated with HCC development in patients with chronic HCV infection.