We conducted a randomized controlled trial of adjuvant interferon therapy in patients with predominantly hepatitis B-related hepatocellular carcinoma (HCC) to investigate whether the prognosis after hepatic resection could be improved. Recurrence is common after hepatic resection for HCC. Interferon possesses antiviral, immunomodulatory, antiproliferative, and antiangiogenic effects and may be an effective form of adjuvant therapy. Since February 1999, patients with no residual disease after hepatic resection for HCC were randomly assigned with stratification by pTNM stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m (IFN-I group) or 30 MIU/m (IFN-II group) thrice weekly for 16 weeks. Enrollment to the IFN-II group was terminated from January 2000 because adverse effects resulted in treatment discontinuation in the first 6 patients. By June 2002, 40 patients each had been enrolled into the control group and IFN-I group. The baseline clinical, laboratory, and tumor characteristics of both groups were comparable. The 1- and 5-year survival rates were 85% and 61%, respectively, for the control group and 97% and 79%, respectively, for the IFN-I group (P = 0.137). After adjusting for the confounding prognostic factors in a Cox model, the relative risk of death for interferon treatment was 0.42 (95% CI, 0.17-1.05; P = 0.063). Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM stage I/II tumor (5-year survival 90% in both groups; P = 0.917) but prevented early recurrence and improved the 5-year survival of patients with stage III/IVA tumor from 24% to 68% (P = 0.038). In a group of patients with predominantly hepatitis B-related HCC, adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors. Further larger randomized trials stratified for stage are needed.