Immunotherapy-based regiments have potential as first-line treatment for advanced gastric esophageal cancer. The present study aimed to conduct a meta-analysis of the association between the efficacy and safety of first-line immunotherapy combined with chemotherapy in patients with unresectable locally advanced or metastatic gastric esophageal cancer. Subgroup analysis of patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) was conducted to identify the characteristics of patients with immune benefit and to provide a decision-making basis for clinical practice. PubMed, Embase, Cochrane Library and other databases were searched to collect randomized controlled trials of immunotreatment-based regimens (experimental group) versus conventional first-line chemotherapy regimens (control group) for unresectable locally advanced or metastatic gastric esophageal cancer. The main outcome measures included progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate and safety, and the secondary outcomes were the differences in OS and PFS between patients with PD-L1 CPS ≥10 and those with PD-L1 CPS <10. In addition, Asian and non-Asian populations were analysed. Nine studies with a total of 6,820 patients were included. The OS of patients treated with immunotherapy-based regimens was significantly longer than that of those treated with chemotherapy alone [HR=0.74; 95% CI (0.69, 0.80); P<0.00001]. The OS of patients with PD-L1 CPS ≥10 and PD-L1 CPS <10 in the experimental group was significantly longer than that of patients in the control group [HR=0.68; 95% CI (0.59, 0.77); P<0.00001 and HR=0.73; 95% CI (0.62, 0.87); P=0.0005]. The PFS of patients being treated with immunotherapy-based regimens was significantly longer than that of those treated with chemotherapy alone [HR=0.71; 95% CI (0.59, 0.86); P=0.0003]. In addition, the PFS of patients with PD-L1 CPS ≥10 and PD-L1 CPS <10 in the experimental group was significantly longer than that of patients in the control group [HR=0.67; 95% CI (0.49, 0.92); P=0.01 and HR=0.63; 95% CI (0.48, 0.83); P=0.001]. There was no significant difference in the overall incidence of adverse events and the incidence of grade 3 or above adverse events between the experimental and control groups [RR=1; 95% CI (0.99, 1.02); P=0.65 and RR=0.97; 95% CI (0.84, 1.12); P=0.69, respectively]. In conclusion, treatment with immunotherapy-based regimens may prolong the OS of patients with unresectable locally advanced or metastatic gastric esophageal cancer and this treatment regimen is safe compared with chemotherapy alone.Copyright: © Duan et al.