Background: Regorafenib improves survival in refractory metastatic colorectal cancer (mCRC), but alternative chemotherapy is required to avoid severe toxicity. S-1+oral leucovorin (SL) has shown promising results in untreated mCRC without severe toxicity. TML trial demonstrated that continuation of bevacizumab (Bev) after progression prolongs overall survival. Thus, we hypothesized that combination chemotherapy of SL/Bev would be beneficial; we conducted a single-center phase II trial to assess the efficacy and safety of SL/Bev as a salvage therapy in mCRC. Methods: Major eligibility criteria were: mCRC with confirmed adenocarcinoma diagnosis; age > 20 years; ECOG performance status, 0–2; and progression after administration or intolerance 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 for 1 week followed by 1 week rest. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. Primary endpoint was disease control rate (DCR). Results: Twenty-three patients were enrolled: 8 (35%) females; median age, 70 years (range, 38–78); and 14 (61%) with KRAS wild-type. DCR was 65% [95% confidence interval (CI), 41.3–82.7%] and response rate was 6% (95% CI, 1.1–27.0%). One patient experiencing partial response to SL/Bev had BRAF mutant tumor with primary resistance to XELOX+Bev as first-line and irinotecan+cetuximab as second-line chemotherapy. Median progression-free and overall survival period were 4.1 and 9.5 months, respectively. Major adverse events were mucositis, (grade 3, 12%), diarrhea (grade 3, 12%), and decreased hemoglobin (grade 3, 12%). Conclusions: SL/Bev was well tolerated and delayed progression; therefore, it can be an alternative chemotherapy for refractory mCRC. We will report the data from final analysis at the meeting. Clinical trial information: 000009083.