The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide as the most common primary hepatic malignancy. In the US approximately one half of all HCC is related to Hepatitis C virus (HCV) infection. The relationship between the primary disease and HCC recurrence after liver transplantation is unknown. We hypothesized that the primary hepatic disease underlying the development of cirrhosis and HCC would be associated with the risk of recurrent HCC after transplantation. A retrospective review was conducted of all primary liver transplants performed at the University of Rochester Medical Center from May 1995 through June 2004. The pathology reports from the native livers of 727 recipients were examined for the presence of HCC. There were 71 liver transplant recipients with histopathological evidence of HCC. These patients were divided in two groups on the basis of HCV status. Group 1 consisted of 37 patients that were both HCV and HCC positive, and Group 2 consisted of 34 patients that were HCC positive but HCV negative. Patient characteristics were analyzed, as well as number of tumors, tumor size, presence of vascular invasion, lobe involvement, recipient demographics, donor factors, pretransplantation HCC therapy, rejection episodes, and documented HCC recurrence and treatment. There were no statistically significant differences between the 2 groups, with the exception of recipient age and the presence of hepatitis B coinfection. The tumor characteristics of both groups were similar in numbers of tumors, Milan criteria status, vascular invasion, incidental HCC differentiation, and largest tumor size. The HCV positive population had a far lower patient survival rate with patient survival in Group 1 at 1, 3, and 5 years being 81.1%, 57.4%, and 49.3% respectively, compared with 94.1%, 82.8%, and 76.4% in Group 2 (p Ο 0.049). Tumor-free survival in Group 1 at 1, 3, and 5 years was 70.3%, 43%, and 36.8% respectively, vs. 88.1%, 73%, and 60.8% in Group 2. In a subgroup analysis, tumor-free survival was further examined by stratifying the patients on the basis of Milan criteria. Group 1 patients outside of Milan criteria had a statistically lower tumor-free survival. By contrast, there was no statistical difference in tumor-free survival in Group 2 patients stratified according to Milan criteria. Cox regression analysis identified HCV and vascular invasion as significant independent predictors of tumor-free survival. Our results suggest that Milan selection criteria may be too limiting and lose their predictive power when applied to patients without HCV infection.