Claudins are involved in the formation of tight junctions in epithelial and endothelial cells. The present study evaluated the expression of claudin 2, 3, 4, and 5 in 20 cases of Paget's disease (13 mammary and 7 extramammary cases), and compared the results with those of other neoplastic skin lesions, including actinic keratoses, basal cell carcinomas, and malignant melanomas. To compare claudin expression in Paget's disease and breast neoplasia, it was also studied in a large set of breast carcinomas. Membrane-bound claudin 3 and 4 expression was seen in all cases of Paget's disease, whereas claudin 5 was seen in 50% of cases and claudin 2 was seen in 32% of cases. In contrast, claudins 3, 4, and 5 were not seen in the other skin lesions, and claudin 2 was seen in most of them, suggesting an inverse expression of these claudins between Paget's disease and epidermal and nevocytic lesions. Claudin expression in breast carcinomas was claudin 2 in 52%, claudin 3 in 93%, claudin 4 in 92%, and claudin 5 in 47%. Claudins 2 and 5 were found more often in ductal carcinomas than in lobular carcinomas. Expression of claudins were frequently associated with each other. They were not associated with estrogen or progesterone receptor status or with tumor grade. No significant differences were found between claudin expression in Paget's disease and breast carcinomas. The results demonstrate that claudins could be useful in diagnosing Paget's disease and in differentiating these lesions from other epidermal lesions, such as actinic keratoses, basal cell carcinomas, and nevocytic lesions. The lack of difference in claudin expression between Paget's disease and breast tumors suggests that changes in the phenotype of claudins 2, 3, 4, and 5 are not necessary for epidermal invasion.