Background: Clinical evidence for PD-L1 positive metastatic or recurrent gastric adenocarcinoma patients were relatively limited in clinic, which limited the development of evidence-based medicine for these patients. Immune checkpoint inhibitor (ICI) therapy has been established as the standard treatment for advanced gastric carcinoma patients recently. Envafolimab is the first approved subcutaneous single-domain PD-L1 antibody, which has been commercialized in China for the treatment of MSI-H/dMMR advanced solid tumors. This study aimed to investigate the efficacy and safety of Envafolimab plus SOX chemotherapy for metastatic or recurrent gastric adenocarcinoma, aiming to provide further reference for clinical rational drug use for this population. Methods: This multi-centre, single-arm, open-label study was conducted to evaluate the efficacy and safety of Envafolimab in metastatic or recurrent gastric adenocarcinoma. A total of 38 patients with histologically confirmed advanced gastric adenocarcinoma were enrolled. Patients will receive Envafolimab (300 mg, s.c., day 1) plus chemotherapy (oxaliplatin 130 mg/m², i.v., day 1, and S-1 40mg, BSA＜1.25 m²、50mg 1.25 m²＜BSA＜1.5 m²、60 mg BSA＞1.5m², p.o., twice daily, days 1-14) every 3 weeks for 6 cycles, followed by maintenance treatment with Envafolimab plus S-1 until disease progression (PD), unacceptable toxicity, or patient refusal. Eligible patients must be histologically confirmed, advanced metastatic gastric adenocarcinoma or recurrent gastric adenocarcinoma after prior surgical treatment. Other key inclusion criteria were previously untreated, HER2-negative, PD-L1 positive (Combined Positive Score (CPS)≥1), ECOG performance status of 0 or 1, and adequate organ function. Patients with any prior ICI therapy, abnormal AFP elevation, or microsatellite-instability-high (MSI-H) status will be excluded. The primary endpoint was objective response rate (ORR) based on the RECIST version 1.1, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), etc. Adverse events were evaluated using the CTCAE v5.0 criteria. Results: Overall, thirteen patients were consecutively enrolled from March, 2022 to September 2022 and involved in this study. The median age was 62.7 years. At present, eight patients were included for efficacy analysis, and nine for safety evaluation. The ORR was 50%, and DCR was 87.5%, based on RECIST v1.1. Survival data are not mature at present. The most common TRAEs were elevated AST (75%), elevated ALT (65%) and leukopenia (42.5%). No treatment-related deaths occurred. Conclusions: Envafolimab plus chemotherapy is a promising and tolerable therapeutic regimen for patients with metastatic or recurrent gastric adenocarcinoma. Clinical trial information: NCT05237349.