This study compares the diagnostic reliability of conventional mucin histochemistry and immunocytochemical techniques in distinguishing mammary Paget's disease from superficial spreading malignant melanoma and primary intraepidermal carcinoma. Formalin-fixed, paraffin-embedded archival tissue was used and comprised 13 cases of mammary Paget's disease, five cases of superficial spreading melanoma, and six cases of intraepidermal carcinoma. Sections from each case were stained for the presence of mucin using diastase periodic-acid-Schiff (d-PAS) with and without an alcian blue counterstain as well as immunocytochemistry for cytokeratin (CAM 5.2), epithelial membrane antigen (NCRC-11) and c-erb B-2 (21N). Mucin staining in intraepidermal carcinoma and malignant melanoma was consistently negative. Diastase-resistant PAS positivity was seen in six of 13 cases of mammary Paget's disease and eight of 13 cases using an alcian blue counterstain. NCRC-11 showed positive immunoreactivity in four of six cases of intraepidermal carcinoma, one in five cases of melanoma, and five of 13 cases of mammary Paget's disease. Positive immunoreactivity using CAM 5.2 and 21N was seen in all cases of mammary Paget's disease, with consistent negative immunoreactivity in the other tumor types. We conclude that CAM 5.2 and 21N should be used in the investigation of mammary Paget's disease in preference to conventional mucin stains.