Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio R ecent epidemiological studies suggest that the presence of diabetes mellitus increases the risk of hepatocellular carcinoma (HCC). 1,2 An explanation for this association may be that diabetes often occurs as part of the metabolic syndrome, which increases the risk of nonalcoholic steatohepatitis (NASH), and that HCC can be a late complication of NASH. 3 Diabetes mellitus is more prevalent among patients with chronic hepatitis C than in the general population. 4 Liver disease contributes to insulin resistance because it leads to a progressive impairment of insulin secretion and it induces hepatic insulin resistance. 5 Studies in transgenic mouse models that harbored the hepatitis C core gene have shown that hepatic insulin resistance may be caused by elevated levels of tumor necrosis factor-alpha, which disturbs the tyrosine phosphorylation of insulin receptor substrate-1. 6 Chronic hepatitis C virus (HCV) infection itself also increases the risk of HCC. It leads to chronic inflammation of the liver, to liver fibrosis, and it may eventually progress to cirrhosis. For patients with hepatitis C cirrhosis the risk for development of HCC is 0.54 to 2.0% per year. 7,8 Abbreviations: anti-HBc, anti-hepatitis B core antigen; BMI, body mass index; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IQR, interquartile range; NASH, nonalcoholic steatohepatitis; OR, odds ratio. From the 1 Erasmus MC University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands; 2 Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; 3 Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany;4 Research and Development (ZonMw) (to B.J.V.).[Stefan Zeuzem is currently affiliated with Johann Wolfgang