BACKGROUND: Immunotherapy is playing an increasing role in the treatment of various cancers. However, its application in rectal cancer is very limited as only microsatellite-unstable bowel cancers with defective mismatch repair are found to benefit. The majority of rectal cancers belong to the microsatellite-stable phenotype. Therefore, the aim of this study is to explore immune-related genes within the tumor microenvironment of rectal cancer, with the objective of discovering novel biomarkers and therapeutic targets for rectal cancer, and to establish a new prognostic prediction model for rectal cancer based on these immune-related genes. METHODS: The data in The Cancer Genome Atlas (TCGA) database were processed using the Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm to obtain differently expressed genes (DEGs). Then the DEGs were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genomes (KEGG), Reactome function enrichment analysis, and protein-protein interaction (PPI) analysis to screen the core genes, which were utilized to compute the risk scores of individual patients. Finally, combining risk scores and clinical characteristics, a new prognostic prediction model was established by univariate and multivariate Cox analyses, and the prognostic model was validated by the Gene Expression Omnibus (GEO) database. RESULTS: The study finally identified four core genes (, , , and ), and immune cell infiltration analyses of the four core genes showed that their expression levels were positively correlated with the distribution of various immune cells. The 4-gene risk score categorized rectal cancer patients into high-risk and low-risk groups, and the results showed that the low-risk group had a stronger correlation with the immune response and had a better prognosis. A prognostic model was developed by integrating risk scores and clinical characteristics and showed a strong predictive effect. CONCLUSIONS: In patients with rectal cancer, , , , and are immune-related core genes, and low expression of each gene is associated with poor clinical prognosis. The risk score obtained on their basis is independent prognostic factors for rectal cancer, suggesting that the four core genes may provide a foundation for the development of new prognostic biomarkers for rectal cancer and the study of immunotherapy.