Locally advanced breast cancer (LABC) was initially characterized as a large primary tumor (≥5 cm), associated with or without skin or chest-wall involvement, fixed axillary lymph nodes, or disease spread to the ipsilateral internal mammary or supraclavicular nodes. Since 2002, LABC has been reclassified to include smaller stage IIB tumors (2 to <5 cm) with lymph node involvement, or stages IIIA-IIIB (≥5 cm) with or without nodal involvement. Despite the rather common presentation of LABC, it remains a poorly understood and highly variable clinical presentation of breast cancer that is a challenge to treatment. Here, we characterized a panel of breast tumors of known stage, grade, and key clinical-pathological parameters for the expression of the protein ezrin, which is involved in promoting signaling of the PI3K-Akt-mTOR pathway in response to extracellular and tumor micro-environmental signals, and is involved in breast cancer invasion and metastasis. We show that ezrin, which resides primarily in the apical membrane in normal breast epithelium, relocalizes primarily to the cytoplasm in >80 % of traditional (T3) invasive ductal LABC tumors (≥5 cm). Cytoplasmic ezrin is very strongly associated with a single characteristic in breast cancer-large tumor size. In contrast, in large non-malignant fibroadenomas, ezrin staining was similar to that of normal breast epithelium. Small (T1, 1 cm) invasive ductal carcinomas displayed largely apical membrane and perinuclear ezrin localization with weak cytoplasmic staining. Cytoplasmic ezrin localization was also associated with positive lymph node status, but no other clinical-pathological features, including hormone receptor status, histological or nuclear grade of tumor cell. The cytoplasmic relocalization of ezrin may therefore represent a novel marker for large malignant tumor size, reflecting the unique biology of LABC.