© 2015 Elsevier Inc. Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P <.0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P =.0002) or ER-/PR+ (P =.0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P =.001) and disease-specific survival (P =.005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine.