Abstract Background The mean 5–6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. Methods Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0–2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80–120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). Results A total of 31 patients were enrolled. DCR was 65 % [95 % confidence interval (CI), 48–100 %] and the response rate was 7 % (95 % CI, 0.7–22 %). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95 % CI, 2.1–9.3] and 9.9 [95 % CI, 7.4–NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26 %) and diarrhea (11 %), which were manageable by dose reduction/interruption. Conclusions SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. Trial registration This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( IDUMIN000009083 ) on 11 October 2012.