Hepatocellular carcinoma with portal venous invasion has a poor prognosis. We report a case treated successfully by intra-arterial 5-fluorouracil with systemic pegylated-interferon-alpha-2b instead of conventional interferon-alpha. A 66-year-old man was admitted to our hospital, and diagnosed with hepatocellular carcinoma with portal venous invasion. Following informed consent, he was treated with eight week cycles of combination chemotherapy using intra-arterial 5-fluorouracil (500 mg/body/day i.a., days 1-5, 8-12 continuously) and pegylated-interferon-alpha-2b (100 microg body s.c., days 1, 8). No significant side effects were observed during his therapy. After 4 cycles, computed tomography scan revealed a partial response of tumor reduction. This is the first report of advanced hepatocellular carcinoma effectively treated using subcutaneous pegylated-interferon-alpha-2b with intra-arterial 5-fluorouracil. While the conventional therapy of interferon-alpha with 5-fluorouracil has significant side effects, no significant side effects were observed in our case. The use of subcutaneous pegylated-interferon-alpha-2b combined with intraarterial 5-fluorouracil, may improve patients' quality of life.