The prognosis of hepatocellular carcinoma(HCC) invading the major branches of the portal vein(Vp3 or 4) is extremely poor. Recently, we reported the efficacy of the combination therapy with subcutaneous interferon(IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3 or Vp4. Forty-eight consecutive patients with HCC and Vp3 or 4 were treated with the combination therapy consisting of continuous arterial infusion of 5-FU(450-500 mg/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN(5 MIU, 3 times/week, 4 weeks). The treatment outcome of these cases was very good. In addition, it is considered direct antitumor effect, the angiogenesis depression effect, and the indirect antitumor effect through immunocompetent cell, may concerned, as the mechanism. In conclusion, combination therapy with subcutaneous IFN and intra-arterial 5-FU is therefore a promising treatment modality for intractable HCC with Vp3 or 4.