Background: Trifluridine-tipiracil (FTD/TPI) plus bevacizumab has shown efficacy inrefractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in Ras mutated population, is limited. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to KRAS status. Methods: Eligible patients were mCRC refractory or intolerant to all standard therapies including fluoropyrimidines, irinotecan and oxaliplatin. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m², twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), PFS, and safety data were collected and analyzed. Results: Forty-two patients were enrolled. Median age was 67 years (range 41–79 years), 44% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, 85% were KRAS and 15% NRAS mutant, and 75% underwent primary tumor resection; 68% of patients had liver metastases, 49% had lung metastases, and 18% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range1–3), and 85% of patients received at least one previous anti-angiogenic agent. DCR was 57.1% (90% CI, 44.6 %-69.3%, P = 0.0690), respectively. The median progression-free survival (PFS) was 4.6 months. The most common grade 3 or higher adverse event was neutropenia (54%), and anemia (16%); 32% of patients required either dose delays or dose reductions due to toxicity. No treatment-related deaths occurred. Conclusions: FTD/TPI is an important therapeutic resource in refractory RAS mutated metastatic colorectal cancer that combines manageability and safety.