BACKGROUND AND AIMS: There is a strong epidemiologic association between diabetes mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic basis for this association has not been established. We sought to evaluate the association between insulin resistance (IR), beta-cell dysfunction, and HCV among orthotopic liver transplant (OLT) recipients. METHODS: We performed a cross sectional analysis comparing 39 HCV(+) with 60 HCV(-) OLT recipients. IR and beta-cell function were calculated using validated measures and were correlated with clinical variables. RESULTS: By multivariate analysis of the entire cohort, HCV infection and body mass index (BMI) were independent predictors of IR (P =0.04 and 0.0006, respectively). HCV infection was associated with 35% increase in IR. Because the model used to calculate IR was derived from nondiabetic subjects, we performed additional analysis of patients who did not meet criteria for diabetes at the time of their study evaluation. In this analysis, HCV(+) subjects had greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 mu U/mL and 3.8) compared with HCV(-) patients (10.7 mu U/mL and 2.5) (P =0.03, 0.03). There was no difference in beta-cell function or hepatic insulin extraction between the HCV (+) and (-) groups. HCV (P =0.0005), BMI (P <0.0001), and high high-density lipoprotein (P =0.039) were the only independent predictors of IR. The presence of HCV infection and a 10-fold increase in HCV RNA were associated with a 62% and 8% increase in IR, respectively. CONCLUSIONS: HCV is independently associated with increased IR after OLT. These findings provide a possible pathogenetic basis for the association of DM with HCV.