Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Zolbetuximab, a new monoclonal antibody against Claudin (CDLN) 18.2 has demonstrated interesting results in clinical trials, however, there is still a need to find a safe and effective first-line treatment, especially for epidermal growth factor receptor (HER) 2-negative patients. Therefore, we aimed to perform a meta-analysis exploring the use of combined immunotherapy (Zolbetuximab) and standard chemotherapy versus chemotherapy alone. Methods: We searched PubMed, Embase and Cochrane Central for randomized controlled trials (RCTs) comparing Zolbetuximab to chemotherapy alone in patients with CLDN18.2-positive gastric or GEJ adenocarcinoma. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Objective Response Rate (ORR) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and risk ratio (RR) for ORR and TEAE, with 95% confidence intervals (CI). Statistical analyses were performed using R software version 4.3.1 with a random-effects model. I² analysis was used to assess heterogeneity. Adverse Events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for AE. Results: From sixty-six studies, three were included, with a total of 1349 patients. 671 (49.7%) were part of the intervention group, 769 (57.0%) were male, 360 (26.7%) underwent prior gastrectomy and 1304 (96.7%) had a more than 70% CLDN18.2 cellular staining rate. Age range was 21-83 years. Treatment with Zolbetuximab was associated with significantly higher PFS (HR 0.64; CI 0.49-0.84; p = 0.0011; I² = 59.6%) and OS (HR 0.70; CI 0.59-0.84; p<0.0001; I² = 40.0%). TEAEs grade ≥ 3 (RR 1.09; CI 1.03-1.16; p = 0.0051; I² =0.0%) were greater for the intervention group. ORR and serious TEAE had no difference when compared with the control group. Most frequent AEs were nausea (34.6%), vomiting (30.2%) and decreased appetite (18.6%). Conclusions: In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.