Epidemiological studies suggest diabetes mellitus (DM) may be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Since diabetes and HCV are common in liver transplant recipients, we sought to examine the unique contribution of HCV infection to risk of de novo diabetes posttransplantation. Using a cohort of 555 liver transplant recipients (median age 49 years, 54% males, 82% Caucasian) without preexisting diabetes from 3 U.S. centers enrolled between 1990 and 1994 and followed for a median duration of 5 years, we determined the incidence of de novo diabetes and the independent predictors of the development of diabetes. De novo diabetes was defined by the use of antidiabetic medications. De novo diabetes developed in 209/555 (37.7%) patients of whom 157 (28.3%) had transient-DM (T-DM) and 52 (9.4%) had persistent-DM (P-DM). Among HCV-infected transplant recipients, de novo T-DM and P-DM developed in 26% and 14%, respectively. HCV was predictive of P-DM (P = .02) but not T-DM. Older age (P = .03) and tacrolimus use (P = .02) were also independent predictors of P-DM. In conclusion, de novo diabetes is common in transplant recipients, but is typically transient in nature. However, among those developing de novo persistent diabetes, HCV is one of the most important risk factors. This adds further support to the epidemiological data linking HCV and diabetes. (Liver Transpl 2004;10:349–355.)