Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age ≥18 years, PS 0–2, ≥1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m2 twice a day on D1–14, oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2 on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7–43.7) and disease control rate was 52.6% (95% CI 31.5–72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7–6.9). Median PFS was 2.6 months (95% CI 2.2–2.9) and median OS was 9.8 months (95% CI 5.3–14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.