BACKGROUND: Estrogen receptor, gross cystic disease fluid protein-15 (GCDFP-15), and mammaglobin are molecular markers generally used to delineate breast origin. However, these breast-specific markers are frequently lost in triple-negative tumors and some metastatic breast carcinomas. Lately, GATA-binding protein 3 (GATA-3) has emerged as a putative marker in the diagnosis of mammary carcinoma, a relatively specific immunomarker for the breast. AIM: The aim of this study was to compare the diagnostic performance of GATA-3 and GCDFP-15 in distinguishing metastatic tumor of breast primary and its diverse molecular subtypes. PATIENTS AND METHODS: GATA-3 and GCDFP-15 immunoexpression was analyzed in 105 cases, which included primary invasive breast carcinomas (n=60), metastatic breast carcinomas (n=25), and metastatic carcinomas other than the breast (n=20). Hormonal receptor studies categorized primary carcinomas into their molecular subtypes. RESULTS: In primary and metastatic breast carcinomas, GATA-3 expression was significantly higher than GCDFP-15 (P<0.0001 and 0.006, respectively). The diagnostic accuracy of GATA-3 and GCDFP-15 to determine breast origin in metastatic tumors was 82.2 and 75.8%, respectively, with a sensitivity of 96 versus 65% and specificity 65 versus 85%, respectively. Using GATA-3 in combination with GCDFP-15 enhanced diagnostic accuracy, sensitivity, and specificity rates to 90, 95, and 85%, respectively. Molecular subgroup significantly influenced GATA-3 reactivity. GATA-3 expression in the triple-negative subgroup, although lower than estrogen receptor-positive tumors, was statistically similar to human epidermal growth factor receptor 2-positive tumors. CONCLUSION: GATA-3 has sensible performance in the diagnostic algorithm to distinguish breast origin particularly when combined with GCDFP-15 to enhance the diagnostic accuracy of the immunohistochemical panel. Hypothetically, GATA-3 seems putative to determine breast origin of a tumor metastasizing from a triple-negative primary.