BACKGROUND: Selected 5-year survival results after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be 70%. Our hypothesis was that liver transplantation is effective for long-term cancer control for HCC. STUDY DESIGN: A 20-year retrospective review of a prospectively collected database was carried out. Demographic data and patient survival were calculated. RESULTS: There were 1,422 liver transplantations performed between January 1990 and April 2011. Of these, 264 had HCC and 157 (59%) were pretreated with transarterial chemoembolization. Recipient age was 55.9 (±7.9) years and 208 (79%) of patients were male. The underlying disease was hepatitis C virus in 155 (58.7%), hepatitis B virus in 16 (6%), alcohol in 21 (8%), and miscellaneous in the remaining 72 cases. The mean number of tumors was 1.8 (±1.7) and the mean largest tumor diameter was 2.3 (±1.3) cm in the explanted liver. One, 5, and 10-year patient survival was 88.5%, 69.1%, and 40.5%, respectively; disease-specific survival was 99.1%, 94.4% and 87.9%; and disease-free survival was 86.0%, 64.6%, and 40.1%. One, 5, and 10-year graft survival was 87.3%, 68.0%, and 41.8%. Nine (3.4%) patients required retransplantation; 75 patients (28.4%) have died, but only 10 of 75 (13.3%) died of recurrent HCC (3.7% of all HCC patients receiving a transplant) and 6 (8%) died of recurrent viral hepatitis. An additional 9 recipients developed recurrence (total HCC recurrence, n = 19 [7%]), 4 of whom died of causes other than HCC. The remaining 5 are disease-free post-treatment (mean 5.5 years after orthotopic liver transplantation). CONCLUSIONS: Orthotopic liver transplantation offers an effective treatment strategy for HCC in the setting of cirrhosis, even in the setting of hepatitis C virus. Hepatocellular carcinoma recurrence is uncommon in properly selected patients and disease-specific long-term survival approaches 90%.