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S-1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against various solid tumors, and preclinical studies have demonstrated activity against hepatocellular carcinoma. We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics, recommended dose, safety and efficacy of S-1. In phase I, the administered dose of S-1 was approximately 64 mg/m2 per day in three patients (level 1) and approximately 80 mg/m2 per day in six patients (level 2). There was no dose-limiting toxicity at level 1, but two patients had dose-limiting toxicity at level 2 (grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest). The recommended dose was finally estimated to be 80 mg/m2 per day. There were no significant differences in the pharmacokinetics of S-1 between patients with Child-Pugh A and those with B. In phase II, five of 23 patients (21.7%) had partial responses. The median progression-free survival and overall survival were 3.7 and 16.6 months, respectively. The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels, hypochromia and thrombocytopenia. In conclusion, S-1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma, warranting further evaluation in randomized clinical trials. (Cancer Sci 2010; 101: 2606–2611)