We used gel electrophoresis to fractionate serum and urine samples of patients with malignant melanoma and of healthy volunteers (controls) and observed that a) all proteins found in the sera of melanoma patients also occurred in the sera of 2 or more healthy volunteers, b) two minor protein bands were present in the sera of 73% of the melanoma patients but in the sera of only 38% of the controls, and c) one major band was present in the sera of 73% of the melanoma patients but in the sera of only 12% of the controls. We characterized these proteins by molecular size and charge. Two proteins, analogous in electrophoretic behavior to those found more frequently in melanoma patients' sera, were observed exclusively in the urine from melanoma patients. The demonstration of such differences in serum and urine proteins warrants the further study of this system as a serologic and/or immunologic test for diagnosis of malignant melanoma.