BACKGROUND: Breast cancer is a highly prevalent tumor worldwide. Mitochondrial permeability transition (MPT)-driven necrosis is a novel type of cell death induced by mitochondrial membrane disruption. The roles of MPT-driven necrosis in breast cancer remain unclear. METHODS: Gene expression and clinicopathologic features were extracted from The Cancer Genome Atlas and Gene Expression Omnibus. We performed a genome landscape analysis of MPT-driven necrosis (MPTdn)-related genes, and a consensus clustering analysis was conducted to construct MPTdn clusters. Next, a risk model was established based on the differentially expressed genes related to MPTdn. We grouped and used external data sets to verify the stability of the model. Subsequently, immune correlation analysis, clinical correlation assessment and drug sensitivity analysis were conducted. Finally, candidate genes were validated in the protein and mRNA levels. RESULTS: A total of 39 MPTdn-related genes were identified in our analysis. Most MPTdn-related genes had different expression levels and somatic mutations in breast cancer, and a close interaction was noted among them. A risk model composed of BCL2A1, SCUBE2, NPY1R and CLIC6 was constructed. The low-risk group had better overall survival and higher immune infiltration levels. All three external data sets achieved excellent predictive efficacy. Finally, the immunohistochemistry results indicated that BCL2A1, SCUBE2, NPY1R and CLIC6 were expressed at significantly lower levels in breast cancer tissues, and the transcriptome sequencing results revealed that BCL2A1 and SCUBE2 mRNA expression levels were greater in the nonrecurrence group. CONCLUSIONS: We developed a risk model with excellent predictive efficacy based on MPTdn and revealed that BCL2A1, SCUBE2, NPY1R and CLIC6 could be used as the biomarkers, laying a solid foundation for investigations of therapeutic targets of breast cancer.