To define the histogenesis of the Paget cell and possibly identify differences in cells from the two sites, six vulvar and 23 mammary specimens from Paget's disease lesions were studied for immunocytochemical antigens. All vulvar and 21 (91%) mammary lesions were strongly reactive for glandular cytokeratin. All lesions showed immunopositive Paget cells with epithelial membrane antigen (EMA). An apocrine antigen, gross cystic disease fluid protein (GCDFP-15), decorated 66.5% and 56.5% of extramammary and mammary lesions, respectively. All vulvar Paget cells stained for carcinoembryonic antigen (CEA), a frequency significantly greater than the 35% in mammary lesions (p = 0.02). However, CEA is expressed by both eccrine and apocrine sweat glands and their tumors. Vulvar Paget cells were negative for lysozyme, casein, lactalbumin, and S100 protein, compared with 9%, 4%, 4%, and 26% in nipple lesions. S100 protein expression is similar to that in mammary ductal carcinoma (32%). The glandular origin of both extramammary and mammary Paget cells is indicated by the presence of glandular cytokeratin, EMA, and CEA. Approximately 60% of all cases in both sites showed evidence of apocrine derivation (GCDFP-15 positivity). Variable antigen expression suggests possible malignant transformation of pluripotent germinative cells able to differentiate in an apocrine or an eccrine direction, or in both.