S-1 is a new oral fluorinated pyrimidine derivate, in which the oral 5-fluorouracil (5-FU) prodrug, tegafur, was combined with two 5-FU-modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil), and potassium oxonate (oteracil), at a molar ratio of 1:0.4:1. The final mechanism of action is exerted by 5-FU. The present study is the first European phase II trial of S-1 in gastric cancer. The primary study objectives were the safety, toxicity and activity of S-1 in non-pretreated patients with gastric cancer. The secondary objective was the duration of response. Patients had to have histologically- or cytologically-verified metastatic or locally advanced, unresectable gastric cancer; S-1 was administered orally twice daily at 40, then 35 mg/m² for 28 days every 5 weeks. The starting dose of 40 mg/m² was found to be intolerable due to significant non-haematological toxicity, and this dose was rapidly reduced to 35 mg/m² twice daily. Of the 7 patients enrolled at the 40 mg/m² level, only 3 were evaluable. At 35 mg/m², a response rate of 26.1% (95% Confidence Interval (CI) 12.0–45.1%) in 23 enrolled patients, and 31.6% (C.I. 14.7–53.0%) in 19 evaluable patients according to an independent radiology review, was found. The median duration of response at 35 mg/m² (6 patients) was 223 days (range, 108–828 days), and of stable disease was 111 days (range 68–411 days). S-1 can be administered with an acceptable safety and toxicity in European patients at a dose of 35 mg/m² days 1 – 28 every 5 weeks and is associated with a moderate response rate similar to the results achieved with other fluoropyrimidines.