BACKGROUND Immune checkpoint inhibitor (ICI) therapy has attracted wide attention in the treatment of malignant tumors. This study was designed to build a prognostic model based on immune-related genes for esophageal adenocarcinoma (EAC). MATERIAL AND METHODS The expression of immune-related differentially-expressed genes (IRDEGs) between EAC and normal samples from The Cancer Genome Atlas database was analyzed. Univariate and multivariate Cox regressions were used to identify the prognostic IRDEGs and construct an immune-related gene signature (IRGS) to predict the overall survival (OS) of EAC patients. Then, the molecular mechanisms and immune characteristics were comprehensively analyzed. RESULTS A total of 111 IRDEGs were obtained from the weighted gene co-expression network analysis. Univariate Cox regression analysis showed that 12 IRDEGs (P<0.05 for all) were linked with OS in the EAC patients. Four genes were used to construct the IRGS based on the multivariate Cox regression analysis. Patients in the high-risk group showed worse OS than those in the low-risk group (P<0.001). A high-risk score was related to DNA replication relevant pathways, an increase in mutation rate, and an increase in activated mast cell infiltration. Patients with high-risk scores had lower tumor immune dysfunction and exclusion scores (P<0.001). CONCLUSIONS IRDEGs may be involved in the progression of EAC. The high-risk group is more suitable for immunotherapy, which may provide a reference value for the treatment of clinical EAC patients. Therefore, it is possible to identify the patients who are better suited for ICI therapy.