We designed an open-label, non-comparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies.From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (n=77) or C-B (n=76). The primary endpoint was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary endpoints included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires) and safety.Median duration of treatment was 7.8 [6.0;9.7] months and 6.2 [4.1;9.1] months in the TT-B and C-B groups, respectively. Median PFS was 9.2 [7.6;11.6] and 7.8 [5.5;10.1] months, respectively. Median OS was 18 [15.2;NA] and 16.2 [12.5;NA] months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% vs. 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% vs. 0% with TT-B) and grade ≥3 diarrhea (8% vs. 1% with TT-B), consistent with the known safety profiles of these agents.TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL.