BACKGROUND: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is characterized by an immunosuppressive tumor microenvironment, leading to limited efficacy of immunotherapy in these patients. Clinical trial data suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients. However, whether these research findings can be "replicated" in clinical practice still requires further validation through real-world studies. This study aims to evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-programmed death 1 (PD-1) immunotherapy as the first-line regimen for MSS mCRC in the real world. AIM: To evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-PD-1 immunotherapy as the first-line regimen for MSS mCRC in the real world. METHODS: We conducted a retrospective analysis of patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital between January 2020 and December 2024. Patients were stratified into two treatment groups: (1) An experimental group receiving first-line chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy; and (2) A control group receiving chemotherapy plus bevacizumab alone. Propensity score matching was employed to balance baseline characteristics, including age, gender, Eastern Cooperative Oncology Group performance status, number of metastatic sites, and primary tumor location. The primary endpoints were progression-free survival and overall survival, while secondary endpoints included disease control rate, objective response rate, and treatment-related adverse events. Survival outcomes were assessed using Kaplan-Meier analysis with log-rank testing. Additionally, inverse probability of treatment weighting was applied for sensitivity analysis to validate the robustness of our findings. RESULTS: The propensity score matching analysis identified 103 well-balanced patient pairs with a median follow-up of 25.5 months. The experimental group demonstrated numerically higher objective response (36.00% 23.08%, = 0.309) and disease control rates (96.00% 91.03%, = 0.6759) compared to the control group, though these differences were not statistically significant. Similarly, no significant survival benefit was observed for either progression-free survival [hazard ratio (HR) = 0.7076, 95% confidence interval (CI): 0.4069-1.23, = 0.22] or overall survival (HR = 1.154, 95%CI: 0.4712-2.827, = 0.75). Multivariate analysis identified liver metastases as an independent poor prognostic factor (HR = 3.36, 95%CI: 1.71-6.60, < 0.001), while subgroup analyses revealed potential benefits of the experimental regimen in male patients (HR = 0.33, 95%CI: 0.14-0.81, = 0.025) and those with right-sided primary tumors (HR = 0.40, 95%CI: 0.17-0.95, = 0.022). Safety profiles were comparable between groups, though elevated lactate dehydrogenase emerged as an independent risk factor for poorer outcomes in the experimental group (HR = 4.11, 95%CI: 1.02-16.55, = 0.046). CONCLUSION: Chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy could not demonstrate promising efficacy in treating MSS mCRC compared to the standard first-line chemotherapy regimen with bevacizumab. Male patients or those with right-sided mCRC may derive benefits from immune-based combination therapy. Further research is needed to investigate specific clinical characteristics or biomarkers to identify patients who may derive benefit from combined immunotherapy approaches.