Breast cancer shows extensive clinical and molecular heterogeneity. Prognostic factors are very important for outcome estimation in individual patients. Nuclear factor κB (NF-κB) and hypoxia-inducible factor 1α (HIF-1α) are transcriptional factors involved in cancerogenesis and in the metastatic spread of tumor cells. The aim of this study was to evaluate the expression of NF-κB and HIF-1α and to correlate the immunohistochemical expression of these markers with the breast cancer subtype and the patient outcome. The retrospective study included 208 cases of ductal invasive breast cancers stratified by the molecular subtype according to the St. Gallen 2011 classification. The Kaplan-Meier survival curve showed that an increased mortality risk was associated with tumors belonging not to the luminal A subtypes but to the Her-2-enriched and luminal B-Her-2-positive subtypes instead (P<0.001). Activation of NF-κB was associated with estrogen-negative tumors (P=0.005). We found a better overall survival in NF-κB-positive tumors in the luminal A subtype (P=0.021). This may be explained as a consequence of a possible tumor-suppressing effect of NF-κB. HIF-1α was related to the overall survival as a poor prognostic factor (P=0.036). In our opinion, the practical relevance of NF-κB and HIF-1α expression as prognostic indicators and potential targets for specific therapies deserve further investigation.