To evaluate the efficacy of methotrexate (MTX)-5-fluorouracil (5-FU), cisplatin (CDDP), and interferon-alpha-2b(IFN alpha-2b) combination therapy, we conducted a clinical pilot study in patients with locally advanced hepatocellular carcinoma (HCC). Sixteen patients, who had received no prior treatment for the HCC, with portal tumor thrombosis in the main trunk or in the major branch were enrolled in the study. IFN alpha-2b (3 x 10(6) units) was injected subcutaneously 3 times per week. After a bolus administration of MTX (30 mg/m2), CDDP (75 mg/m2) and thereafter 5-FU (750 mg/m2) were given weekly by intrahepatic arterial infusion. In 15 eligible patients, there were 1 complete response (CR) and 6 partial responses (PR) with a response rate of 46.7%. Median survival of the 15 patients was 7 months, and the 2-year survival rate of CR and PR patients was 57.1%. There was severe transient hematologic toxicity. More than grade 2 nausea/vomiting was noted in > 50%. In conclusion, the IFN alpha-2b combination chemotherapy demonstrated good response in patients with locally advanced HCC. This treatment should be tried in a controlled study.