Ewing sarcoma (ES) is a malignant bone tumor prevalent among children and adolescents. Disulfidptosis represents a novel form of cell death;​ however, the mechanism of disulfidptosis in ES remains unclear. Our aim is to explore the disulfidptosis-related prognostic signature in ES. Utilizing transcriptomic and clinical data of ES, disulfidptosis-related hub genes (DRHGs) were identified by differential gene expression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. A disulfidptosis-related risk score model (DRRS) was constructed based on these DRHGs. The performance of DRRS was assessed using survival analysis and receiver operating characteristic curve analysis. Immune cell infiltration in different risk subgroups and correlations between DRRS and antitumor reagents were also analyzed. In this study, we developed a disulfidptosis-related prognostic feature based on LRPPRC (leucine rich pentatricopeptide repeat containing), IQGAP1 (IQ motif containing GTPase activating protein 1), NDUFS1 (NADH:​ubiquinone oxidoreductase core subunit S1), and TLN1 (talin 1), which may serve as a predictive and independent risk factor for ES. ES patients in the high-risk group exhibited a poorer prognosis, had a higher proportion of myeloid-derived suppressor cells (MDSCs) and M2 type of tumor-associated macrophages, and showed heightened sensitivity to some antitumor agents such as nilotinib and olaparib. This study is the first to construct a disulfidptosis-related prognostic signature that may predict the prognosis and immune response in ES patients, thereby providing a new reference for understanding the mechanisms of ES and guiding immunotherapy.