Vulvar Paget's disease (VPD) is the most common type of extramammary Paget's disease; however, the frequency of dermal invasion and its clinical significance are unclear, as are the frequency and relationship of an associated regional internal cancer. Thus, we studied the clinicopathologic and immunohistochemical features of 19 patients with VPD. Patients ranged in age from 56 to 86 years (median 65). VPD was entirely intraepithelial (IE-VPD) in 13 patients. Three patients developed IE-VPD recurrence and one developed deeply invasive and metastatic VPD at 10.8 years. Five patients had invasive Paget's disease (INV-VPD) characterized by clinically occult microscopic foci of superficial dermal invasion, ranging in depth from 0.3 to 0.9 mm. All five patients were alive without disease after 12 months to 17 years (median 66 months). A regional internal cancer (CA ASSOC-VPD) occurred in one patient whose VPD was preceded by a deeply invasive grade 3 transitional cell carcinoma of the urinary bladder 9 months earlier. Immunophenotypes of 16 cases with IE-VPD or INV-VPD were CK7+/CK20-/GCDFP15+ in 14 cases and CK7+/CK20+/GCDFP15+ in two cases, with concordant immunophenotypes of the intraepithelial and invasive components in all cases studied. The patient with CA ASSOC-VPD had a CK7+/CK20+/GCDFP15- immunophenotype in the invasive TCC of the urinary bladder and the VPD. We conclude that the predominant form of VPD begins as a primary cutaneous intraepithelial neoplasm that is universally CK7+/GCDFP15+. Foci of unsuspected synchronous dermal invasion by Paget's cells can be expected in almost one third of cases. Subsequent progression into an invasive carcinoma occurs less often. Foci of "minimally invasive" carcinoma (<1 mm) probably do not adversely affect prognosis, whereas deeply invasive carcinoma behaves as a fully malignant adenocarcinoma. The rarer form of VPD appears to result from secondary intraepithelial spread from an associated regional internal carcinoma. The finding of Paget's cells that are CK20+/GCDFP15- suggests the presence of a regional internal carcinoma with a corresponding immunophenotype.