Mammary Paget's disease has been said to result from epidermal spread by contiguity of primary intraductal carcinoma. To assess similar identity, we immunostained Paget's cells and underlying intraductal and/or invasive mammary carcinoma in 20 cases for cytokeratins, epithelial membrane antigen, gross cystic disease fluid protein-15, lysozyme, carcinoembryonic antigen, S100 protein, kappa-casein, and alpha-lactalbumin. Steroid receptor immunostain was positive in only one (5%) of the cases of Paget's disease and in two and four (approximately 15%) (for estrogen and progesterone receptor, respectively) of the cases of ductal carcinoma. In 18 patients (90%), the immunohistochemical profile was identical in Paget's cells and associated carcinoma for seven or more antigens. In one patient, there was a definite disparity in the antigenic profile; in another patient, this was dissimilar because of very focal staining in one site. The antigenic similarity between Paget's cells and underlying carcinoma in 18 (90%) of the cases of mammary Paget's disease suggested in favor of their common origin, ie, probably intraepidermal spread of ductal carcinoma. Origin from apocrine/eccrine structures, or multipotent cells in the epidermis, was suggested in a minority.