BACKGROUND: Stomach adenocarcinoma (STAD) is a common malignant tumor with high morbidity and mortality. Major histocompatibility complex (MHC) is an important component of the immune system responsible for antigen presentation. However, no studies have yet reported on the relationship between major histocompatibility complex-related differentially expressed genes (MHCRDEGs) and the survival prognosis of STAD. The aim of this study is to explore the relationship between MHCRDEGs and survival prognosis in STAD patients. METHODS: Using The Cancer Genome Atlas (TCGA) database, we screened for differentially expressed MHCRDEGs, and a survival prognosis model was constructed based on these genes. We generated training and validation samples from the TCGA and Gene Expression Omnibus (GEO) datasets to enhance the robustness of our findings. The predictive effects of the model were assessed using Kaplan-Meier (KM) survival curve analysis, receiver operating characteristic (ROC) curve analysis, calibration analysis and decision curve analysis (DCA), with statistical significance reported as P values. The differences in the expression of key MHCRDEGs between different subgroups of TCGA and GEO databases were analyzed. Finally, a multifactorial survival prognostic model was constructed by combining MHC score (MHCs), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to verify the expression of key genes. RESULTS: We identified five key MHCRDEGs: CONCLUSIONS: In this study, the expression and distribution of MHCRDEGs in STAD were analyzed by various methods, and a clinical prediction model of STAD was constructed using MHCRDEGs. The validity of this model confirms the feasibility of MHCRDEGs as prognostic markers for STAD, elucidating their potential clinical implications in guiding treatment strategies for this disease.