Background: The alternate-days administration of S-1 was suggested to reduce toxicities such as GI-related adverse events (AEs) or neutropenia maintaining efficacy in some previous reports. This phase II study was aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients with mCRC. Methods: The key eligibility criteria included age ≥75 years, first-line chemotherapy, measurable lesions, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, preserved organ function, and refusal of oxaliplatin- or irinotecan-containing regimen as the initial chemotherapy. Patients received 40 mg (body surface area [BSA] ≤1.25 m²), 50 mg (BSA > 1.25 to ≤1.50 m²), or (BSA > 1.50 m²) of S-1 orally, twice a day, on Monday, Wednesday, Friday, and Sunday every week. Bevacizumab of 7.5 mg/kg was administered every 3 weeks. Primary endpoint was progression-free survival (PFS). Expected median PFS was 8.5 months, and efficacy threshold was 5.0 months. The required sample size was calculated as 50 patients, with a 2-sided type I error of 10% and a power of 80%. Results: Of 54 enrolled patients, 50 patients for efficacy and 53 patients for safety were evaluated. The median age was 79 years (range, 75–88), and 56% had an ECOG PS of 0. The median follow-up time was 34.5 months (95% confidence interval [CI], 25.6–44.9). Median PFS was 8.1 months (95%CI, 7.4–10.1). Median overall survival was 22.8 months (95%CI, 16.9–28.5). The response rate and disease control rate were 44% and 88%, respectively. Grade 3 or more hematologic, non-hematologic, and bevacizumab-related AEs were observed in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Treatment-related death caused by cerebral infarction was observed in one patient. Conclusions: The primary endpoint was met. The alternate-days administration of S-1 combined with bevacizumab was well tolerated and effective in elderly patients with mCRC. Clinical trial information: UMIN000010402.