This study of mammary Paget's disease was carried out with the objects of clarifying its histogenesis and of determining optimal diagnostic measures. Ten consecutive cases of mammary Paget's disease with their underlying ductal carcinomas were compared. Histologic, histochemical, and immunocytochemical examination mainly supported the hypothesis that mammary Paget's disease is an extension of mammary ductal carcinoma into the overlying nipple epithelium. However, two of our ductal carcinomas stained strongly with S-100 protein, while Paget's disease was uniformly negative with this antibody. The significance of this finding is not known. Optimal diagnostic accuracy is obtained by using a combination of routinely stained sections along with a panel of immunocytochemical stains. Nipple wedge biopsy may demonstrate both intraduct carcinoma and Paget's disease, and is thus a superior biopsy technique.