Background: Chemotherapy with capecitabine combined with leucovorin, oxaliplatin, and irinotecan plus bevacizumab (XELOXIRI-Bev) or fluorouracil, leucovorin, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev), is recently introduced as first-line treatment for metastatic colorectal cancer (mCRC). The comparison between the two strategies above in clinical efficacy has not been assessed. Methods: We retrospectively reviewed 138 patients with untreated metastatic colorectal cancer to receive either FOLFOXIR-Bev (group 1) or XELOXIRI-Bev (group 2). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. Results: The mean progression-free survival was 13.5 months in the group 1, as compared with 10.4 months in the group 2 (hazard ratio for progression, 0.3; 95% confidence interval [CI], 0.12 to 0.83; P = 0.032). The objective response rate was 71% in the group 1 and 52.2% in the group 2 (P = 0.006). Overall survival was not found significant difference between the two groups (group 1 vs. 2; 31.3 vs. 24.6 months; hazard ratio for death, 0.6; 95% CI, 0.29 to 1.15; P = 0.115). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the group 1. Conclusion: FOLFOXIR-Bev, as compared with XELOXIRI-Bev, improved the outcomes in patients with mCRC, but increased the incidence of some adverse events.