We conducted a phase II trial of gemcitabine with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate, to evaluate the activity and toxicity of such a combination in metastatic pancreatic cancer (MPC) patients. Patients who had pathologically proven pancreatic cancer with metastatic lesions were eligible candidates for entry into the study. S-1 was given orally (30 mg m(-2)) b.i.d. for 14 consecutive days and gemcitabine (1000 mg m(-2)) was given on days 8 and 15. The cycle was repeated every 21 days. We enrolled 33 MPC patients. The median number of cycles was eight (range 1-20). Grade 3-4 toxicities were leucopenia (33%), neutropenia (55%), anaemia (9%), thrombocytopenia (15%), anorexia (6%), fever (9%), and interstitial pneumonia (6%). Objective responses were obtained in 16 patients (one complete response and 15 partial responses; response rate, 48%; 95% confidence interval (CI), 33-65). Median survival and 1-year survival rate were 12.5 months (95% CI, 5.9-19.1) and 54% (95% CI, 36-72), respectively. Combination chemotherapy with GEM and S-1 was well tolerated and yielded a significantly high response rate.