The cancer testis antigen (CTA), melanoma-associated antigen A3/6 (MAGE-A3/6), is expressed in human cancers of different histologic types, to variable extents, and is an important target for immunotherapy. In this study, to address the potential of MAGE-A3/6 as an immunotherapeutic target in breast cancer (BC), we assessed MAGE-A3/6 expression by PCR in a cohort of 362 primary BC tumors and analyzed the correlation between MAGE-A3/6 expression, tumors hormone receptor (HR) status, and other clinicopathologic features. We found expression of MAGE-A3/6 in 10% of primary BC tumors. MAGE-A3/6 expression was significantly correlated with estrogen receptor (ER) and progesterone receptor (PR) negative status and was frequent in ER (29%) and in PR (24%) tumors. MAGE-A3/6 expression was also significantly associated with high histologic grade but not with patients age, tumor size, tumor type, lymph-node invasion, and human epidermal growth factor receptor 2 (HER2) overexpression. Consistent with the associated poor clinicopathologic features, patients with MAGE-A3/6-expressing tumors had a worse disease-specific survival as compared with patients with MAGE-A3/6 tumors. The frequent expression of MAGE-A3/6 in tumors of patients with primary HR BC, who have, for a large part, limited therapeutic options, encourages the selection of BC patients bearing MAGE-A3/6-expressing tumors for targeted immunotherapy.