Simple Summary CD74 is a transmembrane protein normally expressed in immune cells, and aberrantly expressed in cancer cells. Although CD74 overexpression is mostly associated with hematologic malignancies, some studies have also reported CD74 expression in breast cancer especially associated to the triple negative subtype and metastatic breast cancer. The triple-negative breast cancer is generally more aggressive and with a poorer prognosis than the other subtypes. Immunotherapy holds great promise in clinical management of breast cancer, and CD74 may play a regulatory role in immune system responses. Our results showed that CD74 is associated with expression of programmed cell death ligand 1 (PD-L1), which in turn is involved in preventing anticancer immune responses. Overall, our results indicate that CD74 may be a therapeutic target for the treatment of breast cancer patients, in particular in triple negative breast cancer and metastatic breast cancers, where CD74 is commonly overexpressed. The triple-negative breast cancer (TNBC) subtype, defined as negative for ER, PgR, and HER2, is biologically more aggressive and with a poorer prognosis than the other subtypes, in part due to the lack of suitable targeted therapies. Consequently, identification of any potential novel therapeutic option, predictive and/or prognostic biomarker, or any other relevant information that may impact the clinical management of this group of patients is valuable. The HLA class II histocompatibility antigen gamma chain, or cluster of differentiation 74 (CD74), has been associated with TNBCs, and poorer survival. However, discordant results have been reported for immunohistochemical studies of CD74 expression in breast cancer. Here we report validation studies for use of a novel CD74 antibody, UMAb231. We used this antibody to stain a TMA including 640 human breast cancer samples, and found no association with the TNBC subtype, but did find a positive correlation with outcome. We also found associations between CD74 expression and immune cell infiltration, and expression of programmed death ligand 1 (PD-L1). Given that CD74 may play a role in innate immune system responses and the potential of immunotherapy as a viable treatment strategy for TNBCs, CD74 expression may have predictive value for immune checkpoint therapies.