Ecto-ATPase activities of melanocytes and human melanoma cell lines differing in the stage of progression were compared. A dramatic increase in ecto-ATPase activity above the level of normal melanocytes was demonstrated in the differentiated melanomas and was followed by a gradual decrease with tumor progression. The characteristics of this enzymatic activity were consistent with CD39/ecto-ATP diphosphohydrolase (ATPDase) which was found to be the major ecto-ATP-hydrolysing enzyme in melanomas. Indeed, the expression of CD39 and the level of CD39 mRNA followed a similar pattern. Since CD39 is known to regulate homotypic adhesion and, supposedly, affects the disaggregation step, we suggest that overexpression of CD39 may enable tumor cells to reduce contacts with T-lymphocytes and escape from immunological recognition.