The histogenesis as well as the biological and molecular differences in mammary Paget's disease (MPD) and extramammary Paget's disease (EPD) are not well understood. HER-2/neu oncogene overexpression is associated with poor prognosis in breast cancer patients. It is also believed that the spread of Paget's cells through the epidermis is induced by a motility factor that acts via the HER-2/neu receptor. However, previous studies on HER-2/neu expression in MPD and EPD have given conflicting results. Recent studies have suggested that vimentin expression in breast cancer confers a more aggressive phenotype with a possible role in tumor invasion and metastasis. We examined 58 cases of MPD and EPD for HER-2/neu overexpression and vimentin status to study the role of these markers in the production of the Paget's phenotype. Thirty-five of the 38 cases (92.1%) of MPD were associated with an underlying carcinoma, while none of the cases of EPD were associated with an underlying malignancy. Thirty-six of the 38 cases of MPD (94.7%) overexpressed the HER-2/neu oncoprotein and 17 cases (44.7%) showed vimentin expression. In contrast, only 1 of the 20 cases of EPD (5%) showed positivity for HER-2/neu oncoprotein and all were negative for vimentin. Our results indicate that the cell motility enhancing effect of HER-2/neu oncoprotein and possibly vimentin plays a significant role in the pathogenesis of MPD which appears to be a pagetoid spread of an underlying ductal malignancy (secondary), while EPD is an in situ malignant transformation of a totipotential epidermal cell or glandular epithelium.