Human malignant melanoma cell lines have been divided into three broad groups on the basis of morphology, pigmentation, tyrosinase levels, the 2-dimensional electrophoretic patterns of their [³H]glucosamine-labeled glycoproteins and the presence or absence of an extracellular matrix of fibronectin. The most pigmented cell lines were characterized by the synthesis of a novel glycoprotein with a molecular weight of 75,000 and the absence of a fibronectin matrix. As cultured skin melanocytes also had these characteristics, this group of melanomas appears to be the most differentiated. Melanoma cell lines in the amelanotic group were characterized by the synthesis of high levels of HLA-DR antigen and by the production of an extracellular fibronectin matrix.