The fate of cell surface tumor-associated antigens shed by viable human melanoma cells was studied in vitro. Labeled surface material shed by radio-iodinated melanoma cells was incubated with a variety of unlabeled human cells for 24 hr. Both melanoma-associated antigens (MAAs), quantitated by specific immunoprecipitation, and unrelated surface macromolecules were degraded or inactivated by normal and malignant cells including the melanoma cells themselves. The MAAs studied were particularly susceptible to degradation. Following incubation with a variety of cells, immunoreactive MAAs decreased 2 to 3 times more rapidly than did unrelated surface macromolecules shed concurrently by melanoma cells. However, melanoma cells had a selective defect in their ability to degrade MAAs. Though catabolically active, these cells degraded non-MAA surface macromolecules shed by themselves or by allogeneic cells much more rapidly than they inactivated MAAs. These observations suggest that the ultimate amount of soluble tumor antigens that accumulate in body fluids will depend on the balance between the rate of their release and that of their degradation and that as a result of a selective defect in the catabolic activity of melanoma cells some tumor antigens may be particularly prone to accumulate in the extra-cellular fluid bathing these tumors.