The MUC18 antigen is an integral membrane glycoprotein of 113 kDa whose expression on primary human melanomas correlates with poor prognosis and the development of metastatic disease. MUC18 is expressed only sporadically in benign melanocytic nevi and thin primary melanomas that have a low probability of metastasizing. However, with increasing tumor thickness, MUC18 expression becomes more frequent and it is found on 80% of advanced primary tumors and metastases. MUC18-encoding cDNA clones were obtained by screening a human melanoma phage lambda expression library with monoclonal antibodies produced against the denatured antigen. The deduced sequence of 603 amino acids consists of a signal peptide, five immunoglobulin-like domains, a transmembrane region, and a short cytoplasmic tail. The highest sequence similarity is with a group of nervous system cell adhesion molecules, which includes neural cell adhesion molecule (N-CAM). The close structural relationship with these molecules suggests that MUC18 may also be a developmentally regulated cell adhesion molecule.