Melanoma can show a broad spectrum of immunoreactivity and exhibit aberrant expression of antigens or changes in immunophenotype, particularly at metastatic sites. We studied 70 primary melanomas and their metastases with a broad panel of immunohistochemical markers using a tissue microarray technique to determine possible antigenic shift between the primary lesions and their metastases. Representative tissue cores were taken and processed from each case, and the tissue microarrays were stained by standard methods using antibodies to vimentin, bcl-2, CD117, carcinoembryonic antigen, epithelial membrane antigen, S-100 protein, HMB-45, cytokeratin AE1/AE3, Melan-A, TTF-1, CD99, and tyrosinase. Histologically, all the melanomas were of the classic epithelioid type. A slight increase in the expression of Melan-A was noted in metastatic lesions as opposed to the primary tumors (63% vs. 48.4%). Expression of other melanoma-associated markers, including S-100 protein and tyrosinase was only slightly decreased at metastatic sites as opposed to the primary tumor. Increased aberrant expression of epithelial-associated markers, including epithelial membrane antigen and cytokeratin AE1/AE3 was also noted in the metastases. bcl-2, CD117, and TTF-1 also showed a modest increase in antigenic expression at metastatic sites over the primary lesions. The results of this study demonstrated minimal antigenic shift between primary and metastatic melanoma for some of the more conventional melanocytic markers, it showed increased expression of aberrant markers and oncogene expression at metastatic sites.