Despite the recognition of numerous factors for aggressive hepatitis C virus (HCV) recurrence after liver transplantation (LT) our understanding of this phenomenon is incomplete. We tested the hypothesis that diabetes mellitus (DM) was implicated. One hundred sixty-three patients undergoing primary LT for HCV from 1990 to 2004 were evaluated and biopsies were scored according to the modified Ishak score. Severe recurrence of HCV was defined as a fibrosis score > or = 4 within 6 years of LT. Risk factors assessed included recipient, donor and transplant variables. Fifty-four patients (33.1%) had a fibrosis score > or = 4 at the end of the study period. Factors associated with progression to severe fibrosis was donor age (p = 0.008) especially donor age >55 (p = 0.038, HR 2.43), pre-LT DM (p = 0.039, HR 2.68) and DM post-LT (p = 0.004, HR 3.28). The combination of receiving a liver from a donor older than 55 years and having DM post-LT was associated with an 8.38-fold risk of progression to severe fibrosis (p = 0.000124) when compared to patients not diabetic post-LT who received livers from donors aged <55 years. These data indicate that diabetic status is one of the more important variables determining the severity of HCV recurrence and is synergistic with donor age. This observation may provide an additional management opportunity to modify the impact of HCV recurrence.