This study aimed to investigate the potential prognostic value of DNA damage repair genes (DDRGs) in esophageal squamous cell carcinoma (ESCC) and their relationship with immune-related characteristics.We analyzed DDRGs of the Gene Expression Omnibus database (GSE53625). Subsequently, the GSE53625 cohort was used to construct a prognostic model based on least absolute shrinkage and selection operator regression, and Cox regression analysis was used to construct a nomogram. The immunological analysis algorithms explored the differences between the potential mechanism, tumor immune activity, and immunosuppressive genes in the high- and low-risk groups. Of the prognosis model-related DDRGs, we selected PPP2R2A for further investigation. Functional experiments were conducted to evaluate the effect on ESCC cells in vitro.A 5-DDRG (ERCC5, POLK, PPP2R2A, TNP1 and ZNF350) prediction signature was established for ESCC, stratifying patients into two risk groups. Multivariate Cox regression analysis showed that the 5-DDRG signature was an independent predictor of overall survival. Immune cells such as CD4 T cells and monocytes displayed lower infiltration levels in the high-risk group. Additionally, the immune, ESTIMATE, and stromal scores in the high-risk group were all considerably higher than those in the low-risk group. Functionally, knockdown of PPP2R2A significantly suppressed cell proliferation, migration and invasion in two ESCC cell lines (ECA109 and TE1).The clustered subtypes and prognostic model of DDRGs could effectively predict the prognosis and immune activity of ESCC patients.© 2023. The Author(s).