Background: The aim of this multicenter, single-arm phase II trial was to investigate the efficacy and safety of S-1 plus bevacizumab (BEV) as a salvage treatment for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies. Methods: Patients who had unresectable mCRC with mutant-type KRAS; were refractory to fluoropyrimidine, irinotecan, oxaliplatin; and had previous treatment with BEV were enrolled and received S-1 plus BEV therapy (bevacizumab 7.5 mg/kg on day 1 and S-1 40-60 mg bid on day 1-14, every 3 weeks). The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), tumor response, and safety. Results: A total of 27 patients were enrolled. After a median follow-up period of 12.3 months, the events of disease progression and death occurred in 26 patients (96%) and 20patients (74%), respectively. The median number of treatment cycles was 3 (range, 1-17 cycles). Median PFS was 2.3 months (95% confidence interval [CI], 2.2-2.4 months), and the median OS was 7.7 months (95% CI, 4.3-10.1 months). The overall response and disease control rates were 0% and 33%, respectively. The median tumor shrinkage rate (DpR) was -15% (range, -59 to 15%). The frequencies of hematological and non-hematological adverse events above grade three were 25% and 8%, respectively. Conclusions: S-1 plus BEV therapy could be feasible salvage line treatment for Japanese patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000006476.