Claudins are a family of transmembrane proteins involved in cell-to-cell adhesion and are believed to be the main component of tight junctions. Recent studies have suggested that some metastatic solid tumors lack claudin expression. It is unknown whether claudins play a role in cutaneous melanoma. Immunohistochemical studies were performed on tissue microarrays containing 19 benign melanocytic nevi (BN), 21 dysplastic nevi (DN), 23 primary malignant melanomas (MMs), and 31 metastatic melanomas (MMMs) using a polyclonal anti-claudin-1 antibody. Immunoreactivity in tumor cells and associated vessels was graded by intensity and by percentage of reactive cells. Normal epidermis served as internal control (3+ labeling). Cases with at least 2+ labeling in more than 25% of the cells were considered positive. Claudin-1 expression was present in 37% of BN, 24% of DN, 26% of MM, and 3.2% of MMM. Tumor-associated vessels showed the following results: 11 of 19 (58%) in BN, 14 of 21 (67%) in DN, 17 of 23 (74%) in MM, and 6 of 31 (19%) in MMM. A significant loss of expression was noted between MMM and all other lesions in tumor cells and associated vessels. There was no significant difference between BN, DN, and MM. Within primary melanomas, there was a significant correlation between expression of claudin in tumor cells and Clark level/Breslow thickness. Also significant was a decreased expression of claudin in tumor vessels of lesions with higher Breslow thickness or Clark level. These data suggest that loss of claudin-1 may play a significant role in the acquisition of metastatic phenotype in cutaneous melanoma. Cohn ML, Goncharuk VN, Diwan AH, Zhang PS, Shen SS, Prieto VG. Loss of claudin-1 expression in tumor-associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasms.