The cell surface adhesion molecule MCAM (MUC18) is strongly expressed by advanced primary and metastatic melanomas but is weaker and less frequent in nevus cells. Previous studies have shown that MCAM expression correlates with tumor thickness and metastatic potential of human melanoma cells in nude mice. To provide direct evidence that MCAM plays a role in tumor growth and metastasis of human melanoma, the nonmetastatic MCAM-negative primary cutaneous melanoma SB-2 cells were transfected with MCAM cDNA and analyzed subsequently for changes in their tumorigenic and metastatic potential. Enforced expression of MCAM in SB-2 cells rendered them highly tumorigenic and increased their metastatic potential in nude mice as compared with parental and control transfected cells. The transfected cells displayed increased homotypic adhesion, increased attachment to human endothelial cells, decreased ability to adhere to laminin, and increased invasiveness through Matrigel-coated filters. Anti-MCAM monoclonal antibody reversed these functions in the transfected cells but not in control cells. The above changes in function attributed to the expression of MCAM may underlie the contribution of MCAM/MUC18 to the malignant phenotype.