We have reported a remarkably high anti-tumor efficacy using intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat advanced hepatocellular carcinoma (HCC) with portal vein thrombus. However, we have been confirming distant metastases along with a prognosis extension as hepatic lesions could possibly be controlled to a certain extent. Even though there has been no effective chemotherapy against hepatocellular carcinoma with distant metastases, we performed S-1 and interferon-alpha combination chemotherapy for the cases where good results were exhibited from interferon-alpha combined with arterial 5-FU infusion. As a result, we confirmed CR in the anti-tumor effect against distant metastases with no severe adverse effects. It was suggested that a combination therapy of S-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastases.