Background: FOLFOXIRI plus bevacizumab (Bev) is highly effective for treating patients (pts) with metastatic colorectal cancer (mCRC); however, high incidences of hematologic adverse events (AEs) and pump infusion of 5-FU q2wk can complicate treatment continuation. According to the safety lead-in (Step 1), CAPOXIRI plus Bev with 1600-mg/m² capecitabine (Cap), 130-mg/m² oxaliplatin (Ox), 200-mg/m² irinotecan (Iri), and 7.5-mg/kg Bev q3wk was the recommended phase 2 dose (Kotani D, et al., Invest New Drugs, 2021). Here, we report the results of the randomized phase II part (Step 2) of the QUATTRO-Ⅱ study, which examined the efficacy and safety of CAPOXIRI + Bev versus FOLFOXIRI + Bev. Methods: Enrolled pts were ECOG PS 0 or 1, and had chemotherapy-naïve mCRC with wild-type or single heterozygous UGT1A1 *6/*28 genetic polymorphism. Pts were randomly allocated to FOLFOXIRI + Bev (Arm A) or CAPOXIRI + Bev (Arm B) in a 1:1 ratio. The induction treatment in Arm A /B was continued for 8/6 cycles (12/8 cycles at maximum if feasible), and the maintenance treatment was either 5-FU + leucovorin + Bev or Cap + Bev at the discretion of the investigators. The primary endpoint was progression-free survival (PFS), with the two groups deemed equivalent if the hazard ratio (HR) of the point estimate was 0.8 < HR < 1.25. Secondary endpoints were overall survival (OS), overall response rate (ORR), early tumor shrinkage (ETS), depth of response (DpR), and safety. Results: From June 2020 to June 2021, 103 pts (Arm A/B, 51/52 pts) were randomly assigned. Baseline characteristics, including age (median 60 years in both arms) and ECOG PS 0 (90%/94%), were well balanced between arms. At a median follow-up of 23.7 months, the median PFS (Arm A/B) was 10.6 months (95% CI 7.7–13.3)/10.9 months (95% CI 9.3–14.3; HR 1.119, P = 0.639), and the primary endpoint was met (HR: 0.8 < 1.119 < 1.25). The 2-year OS rate (Arm A/B) was 65.5% (95% CI 49.5–77.6)/74.3% (95% CI 59.8–84.2), with the median OS not reached. Moreover, the ORR was 76.5% (95% CI 62.5–87.2)/84.6% (95% CI 71.9–93.1), ETS was achieved in 71.4%/82.0% of pts, and the median DpR was 43.0%/54.2%. Incidences of major grade ≥3 AEs (Arm A/B) were as follows: neutropenia (68.6%/40.4%), febrile neutropenia (9.8%/11.5%), diarrhea (7.8%/17.3%), and appetite loss (7.8%/17.3%). No treatment-related deaths occurred. Conclusions: The efficacy of CAPOXIRI + Bev was comparable to that of FOLFOXIRI + Bev. Although CAPOXIRI + Bev was associated with increased incidences of certain nonhematologic AEs, it was well tolerated, with a decreased incidence of neutropenia and no unexpected safety signal. Good survival and response results suggest that CAPOXIRI + Bev could become a new first-line treatment option in pts with mCRC. Clinical trial information: NCT04097444.