Background: Immunotherapy significantly improved survival in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC). However, whether the addition of immunotherapy to the current standard-of-care treatments can improve efficacy in pMMR/MSS mCRC, the predominant type of mCRC, is unclear. This study aimed to compare the efficacy of serplulimab, a novel PD-1 inhibitor, plus HLX04, a bevacizumab biosimilar, and XELOX versus placebo plus bevacizumab and XELOX as first-line treatment for mCRC. Methods: This was a randomized, double-blind, multicenter phase 2/3 study; current report will focus on the phase 2 part. Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomized 1:1 to receive serplulimab (300 mg, Q3W IV) plus HLX04 (7.5 mg/kg, Q3W IV) and XELOX (group A) or placebo plus bevacizumab and XELOX (group B). Randomization was stratified by PD-L1 expression level (CPS <1 vs. 1≤ CPS <50 vs. CPS ≥50), ECOG PS score (0 vs. 1), and primary tumor site (left- vs. right-sided). The primary endpoint was IRRC-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: Between July 16, 2021 and January 20, 2022, 114 patients were enrolled and randomly assigned to group A (n=57) and group B (n=57). 83 (72.8%) patients were male. All patients had stage IV CRC, and 90 out of the 94 (95.7%) with available MSI status were MSS. Current report will focus on efficacy and safety findings in the modified intention-to-treat population, which included only patients who received study treatment (group A, n=55; group B, n=57). As of June 1, 2023 (data cutoff), median follow-up duration was 17.7 months. IRRC-assessed median PFS was longer in group A than in group B (17.2 vs. 10.7 months; stratified HR 0.60, 95% CI 0.31–1.14). Median OS was not reached in either group (stratified HR 0.77, 95% CI 0.41–1.45). 36 (65.5%) patients in group A and 32 (56.1%) in group B had grade ≥3 treatment-related adverse events (AEs), most commonly neutrophil count decreased (21.8% vs. 10.5%) and platelet count decreased (16.4% vs. 10.5%). Grade ≥3 immune-related AEs were reported for 5 (9.1%) patients in group A and 1 (1.8%) in group B. Treatment-related deaths occurred in 4 (7.3%) patients in group A and 3 (5.3%) in group B. Conclusions: Serplulimab plus HLX04 and XELOX prolonged PFS compared to placebo plus bevacizumab and XELOX. Improvements in other efficacy endpoints were also observed with a manageable safety profile in patients with mCRC. Serplulimab plus HLX04 and XELOX is a promising first-line treatment option for mCRC patients that warrants further investigation. Clinical trial information: NCT04547166.