We retrospectively reviewed to investigate the efficacy and toxicity of monotherapy with S-1 in patients with advanced or recurrent gastric cancer after failure of first-line chemotherapy. Twenty-one patients were evaluated. The median number of treatment cycles was 2 (range 1-19). There were no cases showing either complete or partial response, and 10 patients (47.6%) showed stable disease. The median progression-free survival was 89 days. Sixteen patients (76%) received third-line chemotherapy. The median survival time was 271 days after the initiation of S-1, with a 1-year survival rate of 32%. Hematological toxicities were Grade 4 anemia (9.5%), Grade 3 or 4 neutropenia (9.5%) and leukopenia (4.7%). As for non-hematological toxicities, Grade 3 or 4 diarrhea and anorexia were noted in 9.5% and 14.2% of the patients, respectively. S-1 was found to show no efficacy and cannot be recommended for second-line chemotherapy against gastric cancer.