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Objective: To investigate the clinical efficacy, toxicity and prognosis of SOX regimen (Oxaliplatin plus S-1) combined with Pabolizumab in the treatment of patients with metastatic gastric cancer. Methods: The clinical data of 107 patients with advanced metastatic gastric cancer admitted to Wuxi Branch of Ruijin Hospital Shanghai Jiao Tong University School of Medicine from May 2020 to May 2024 were retrospectively collected. According to the treatment methods, the patients in the chemotherapy group (n=56) only received SOX chemotherapy, and the patients in the combined group (n=51) were given SOX chemotherapy combined with Pembrolizumab. The differences of objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), grade Ⅲ-Ⅳ toxicity and quality of life improvement rate between the two groups were analyzed and compared. Results: According to the efficacy evaluation criteria of RECIST1.1, among all subjects, there were 1 case of complete response (CR) and 21 cases of partial response (PR) in chemotherapy group, 2 cases of CR and 31 cases of PR in combination group. The objective response rate (CR+PR%) in combination group was significantly higher than that in chemotherapy group (64.7% vs 39.3%, P=0.015). Stratified analysis showed that in patients with PD-L1 combined positive score (CPS) ≥1, the ORR of the combination group further increased to 75.9% (22/29), with a more significant advantage than the ORR of 38.9% (14/36) in the chemotherapy group (P=0.004). Survival analysis showed that among all enrolled patients, median PFS and median OS in combination group were 9.3 months and 17.4 months respectively, which were significantly longer than 8.4 and 13.1 months in chemotherapy group (PFS: P=0.020; OS: P=0.011). In addition, among patients with PD-L1 CPS ≥1, the median PFS and OS of the combination group showed a more significant advantage in prolonging compared to the chemotherapy group (median PFS: 10.7 months vs 8.2 months, P=0.003; median OS: 19.0 months vs 12.8 months, P=0.005). Among all enrolled patients, 14 cases showed improvement in quality of life in the chemotherapy group and 23 cases in the combination group, and the improvement rate of quality of life in combination group was significantly higher than that in chemotherapy group (45.1% vs 25.0%, P=0.029). There was no statistical difference in the incidence [67.9% (38/56) in chemotherapy group vs 78.4% (40/51) in combination group] of grade Ⅲ-Ⅳ toxicity between the two groups (P=0.219). Conclusion: In patients with PD-L1 CPS ≥1 or all enrolled patients, compared with chemotherapy alone, SOX regimen combined with pembrolizumab in the treatment of metastatic gastric cancer can significantly improve ORR, prolong PFS and OS, improve prognosis and quality of life, while the toxicity has not increased significantly.