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. METHODS 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%.