This is the first phase II study of S-1 monotherapy for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. The initial dose of S-1 was 35 mg m-2, administered twice daily for 14 days every 3 weeks. Treatment was repeated until the occurrence of disease progression. Twenty-eight patients were enrolled. S-1 was administered to 21 patients as third-line therapy and to the remaining seven patients as fourth-line therapy. Of 26 evaluable patients, the overall response rate was 14.3% (95% CI, 0.4-28.1), and the disease control rate was 42.9% (95% CI, 23.3-62.4). With a median follow-up period of 227 days, median time to progression and overall survival duration were 91 and 414 days, respectively. The 1-year survival rate of all patients was 60.7%. There was no grade 4 toxicity. Grade 3 haematological toxicities were documented only in two patients. In conclusion, S-1 shows potential as a salvage regimen in heavily pretreated colorectal cancer patients. The twice-daily dose of 35 mg m-2 was well tolerated and can be used in designing further combination chemotherapy.