A 57-year-old man with generalized, subcutaneous fat necrosis was found at autopsy to have islet cell carcinoma of the pancreas. The histologic diagnosis of islet cell carcinoma was confirmed by the finding by electron microscopy of characteristic intracytoplasmic granules within pancreatic neoplastic cells. Lipase levels were elevated in serum as well as in tissues in areas of subcutaneous fat necrosis. Enzyme histochemical stains for alkaline and acid phosphatase, leucine aminopeptidase, succinic dehydrogenase, and indoxyl and nonspecific esterase were positive in the areas of subcutaneous fat necrosis. This is the first report of the association of islet cell carcinoma of the pancreas with generalized subcutaneous fat necrosis.