We report a case of recurrent hepatocellular carcinoma (HCC) successfully treated with a combination therapy of interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU), which was administered intravenously. A 49-year-old Japanese man who underwent a right hepatectomy for HCC developed tumor recurrence in the liver 19 months after surgery. Abdominal CT revealed multiple metastatic lesions in the liver. He received a combination therapy of 500 mg/day of 5-FU that was given intravenously by continuous infusion and 5 x 10(6) units of IFN-alpha, given three times weekly. The treatment resulted in a fall in serum PIVKA-II (protein induced by vitamin K antagonism) levels from 337 mAU/ml to 65 mAU/ml and disappearance of tumor stain in enhanced CT. 5-FU is usually administered by arterial infusion in a combination therapy of IFN-alpha and 5-FU. However, 5-FU infusion may be possible intravenously in the combination therapy of IFN-alpha and 5-FU for the treatment of advanced HCC.