Expression of activated leukocyte cell adhesion molecule (ALCAM)/CD166 correlates with the aggregation and metastatic capacity of human melanoma cell lines (Am J Pathol 1998, 152:805-813). Immunohistochemistry on a series of human melanocytic lesions reveals that ALCAM expression correlates with melanoma progression. Most nevi (34/38) and all thin melanomas studied (Clark levels I and II) did not express ALCAM. In contrast, immunoreactivity was detected in the invasive, vertical growth phase of 2 of the 13 Clark level III lesions tested. The fraction of positive lesions further increased in Clark level IV (13/19) and in Clark level V (4/4) lesions. ALCAM expression was exclusively detectable in the vertical growth phase of the primary tumor. In melanoma metastases, approximately half of the lesions tested (13/28) were ALCAM positive. According to the Breslow-thickness, ALCAM expression was observed in less than 10% of the lesions that were thinner than 1.5 mm and in over 70% of the lesions that were thicker than 1.5 mm. Our results strongly suggest that ALCAM plays an important role in melanocytic tumor progression and depict it as a new molecular marker for neoplastic progression of primary human melanoma.