We report a case of diffuse type advanced hepatocellular carcinoma (HCC), which was successfully treated by a combination therapy of interferon-alpha (IFN) and 5-fluorouracil (5-FU). A 74-year-old man underwent distal gastrectomy 6 years ago for gastric cancer. In April 2002, an increased serum alpha-feto-protein (AFP) level was noted and a computed tomography (CT) of the abdomen revealed a diffuse type of HCC. He was treated with a combination therapy of IFN (5x10(6) units/body i.m., days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26) and 5-FU (500 mg/body/day i.a., days 1-5, 8-12 continuously). The treatment was repeated every 4 weeks with a maximum of five cycles. After 5 cycles, serum AFP levels fell from 665 ng/ml to a normal level. CT showed a reduced size of the tumor. He has been well and continue to receive IFN (3x10(6) units/body i.m., two times a week) and 5-FU (500 mg/body/day i.a., once a week) at the outpatient clinic for the last 16 months.