Previous studies provided a direct experimental evidence for the contribution of HCV core protein in the development of insulin resistance (IR), but the clinical impact of HCV core region on IR is still not clear. The present study evaluated the impact of Amino acid (aa) substitutions of HCV-1b core region on IR in 123 Japanese patients infected with HCV-1b without cirrhosis and diabetes mellitus, and investigated the treatment efficacy of 48-week pegylated interferon (PEG-IFN) plus ribavirin (RBV) according to HOMA-IR values. Patients with IR (HOMA-IR ≥2.5) and severe IR (HOMA-IR ≥3.5) were present in 51.2% and 27.6%, respectively. Multivariate analysis identified body mass index (≥25 kg/m2) and hepatocyte steatosis (≥5%) as significant determinants of IR. Furthermore, multivariate analysis identified hepatocyte steatosis (≥5%), aa substitutions of the core region (Gln70 (His70) and/or Met91), and age (≥55 years) as significant determinants of severe IR. Especially, significantly lower proportions of patients with Gln70 (His70) and/or Met91 were noted among those without severe IR (59.6%) than those with severe IR (82.4%). The rates of sustained virological response in patients with IR (50.0%) were not significantly different from those without IR (52.9%). Furthermore, the rates of non-virological response in patients with IR (28.9%) were not significantly also different from those without IR (20.6%). In conclusion, the present study indicated that substitutions of HCV-1b core region were the important predictor of severe IR in patients without cirrhosis and diabetes mellitus, but HOMA-IR values might be not useful as predictors of 48-week PEG-IFN plus RBV therapy. J. Med. Virol. 81:1032–1039, 2009. © 2009 Wiley-Liss, Inc.