The efficacy and safety of S-1 monotherapy for patients with advanced or recurrent non-small cell lung cancer (NSCLC) after the failure of two or more prior chemotherapy regimens were investigated. Records of 36 patients with advanced or recurrent NSCLC who received S-1 monotherapy between January 2005 and December 2008, following the failure of previous chemotherapy, were reviewed retrospectively at two institutions. S-1 was given orally twice daily on days 1-28 every six weeks; the dose was based on body surface area. The median number of prior chemotherapy regimens was three (range 2-5), and that of courses given per patient was two (range 1-10). No patient achieved complete response, 4 patients (11.1%) achieved partial response, 10 patients (27%) had stable disease and 18 patients (50%) had progressive disease. The median progression-free survival was 3 months and the median overall survival was 15.2 months. No grade 4 hematological toxicity was noted. Grade ≥3 non-hematological toxicities were observed in 5 patients (13.9%). No deaths related to S-1 monotherapy occurred. S-1 monotherapy exhibits activity with acceptable toxicity as third-line or subsequent chemotherapy for advanced NSCLC.