Background Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC. Methods Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 80 mg/m 2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m 2 and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS). Results Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval CI 8.7–37.9), and the disease control rate was 76.5 % (95 % CI 58.8–89.3). The median PFS was 5.6 months (95 % CI 3.8–7.0). The median overall survival was 16.4 months (95 % CI 8.1–20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred. Conclusions The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.