Breast cancer (BC) is one of the most common tumor types and has poor outcomes. In this study, a ubiquitination-related prognostic signature was constructed, and its association with immunotherapy response in BC was explored. A list of ubiquitination-related genes was obtained from the molecular signatures database, and a ubiquitination-related gene signature was obtained by least absolute shrinkage and selection operator Cox regression. The genes, , , and , had significant influence on BC outcomes. Patients were categorized into two clusters-a high-risk group with poor survival and a low-risk group with greater chances of controlling BC progression. Univariate and multivariate Cox regression analyses revealed that the risk signature was an independent prognostic factor for BC. Gene set enrichment analysis suggested that the high-risk group was enriched in cell cycle and DNA replication pathways. The risk score was positively linked to the tumor microenvironment and negatively correlated with the immunotherapy response. The IC50 values for rapamycin were higher in the low-risk group, whereas those for axitinib, AZD6244, erlotinib, GDC0941, GSK650394, GSK269962A, lapatinib, and PD0325901 were higher in the high-risk group. Therefore, the ubiquitination-related signature is considered a promising tool for predicting a BC patient's immunotherapy response.