To determine the efficacy and tolerance of irinotecan in combination with S-1 (IRIS) for patients whose disease progressed after treatment with an oxaliplatin-based therapy for colorectal cancer (CRC). Each patient's disease had progressed after the administration of a regimen containing oxaliplatin and 5-FU. S-1 was administered orally at a fixed dose of 40 mg/m(2) twice daily on days 1-14 and 21-35. Irinotecan (150 mg/m(2)) was administered via intravenous infusion on days 1, 15, and 29. Courses were repeated every 6 weeks. 20 patients were enrolled in this study between April 2006 and March 2008. The median age was 63 years (range: 34-74), and the dominant metastasis sites were the liver, lung, and lymph nodes. The objective response rate was 20%; 1 patient registered complete response and 3 patients registered partial responses; 7 patients were stabilized (35%); and 9 evidenced progression of disease (45%). Median progression-free survival was 3.0 months (95% CI, 2.1-3.9 months) and median overall survival was 9.8 months (95% CI, 6.3-13.3 months). For the 41 cycles analyzed, the most commonly detected hematologic toxicity was grade I-II anemia (63.4%). Leukopenia occurred in 18 cycles (41.5%), including eight cycles (19.5%) of grade 3-4 leukopenia. Frequently observed non-hematologic toxicities included the following: grade I vomiting was reported in 4 patients (20%), grade 2 neuropathy occurred in 3 patients (15%), and grade 2 mucositis was noted in 2 patients (10%). Two patients died from sepsis and hematemesis during treatment. Although the response rate in stage I reached the target (≥ 3/18, p0 = 10%) established for movement to stage II, this study had to be discontinued because two patients died during treatment. Additionally, the follow-up loss rate was higher (16.6%) than we had anticipated (<10%). Even though a regime consisting of irinotecan combined with S-1 (IRIS) has proven effective in oxaliplatin-pretreated patients with advanced CRC, treatment-related mortalities and the high follow-up loss rate suggested that this IRIS protocol should result in early closure and modification.