We describe a rare case of hypoglycemia associated with a high molecular weight form of insulin-like growth factor II (big IGF-II) produced during the development of malignant fibrous histiocytoma (MFH). A 66-year-old man was referred to our department for further evaluation of hypoglycemia. At the age of 59, he had been diagnosed as having a MFH in the retroperitoneum, and underwent incomplete resection of the tumor. He had no symptoms of hypoglycemia at that time. Within the last few years, he developed symptoms of hypoglycemia in the early morning. Computerized tomography scans of the abdomen showed multiple tumors around the peritoneum and the liver. Serum insulin levels were decreased although no other hormonal deficiencies were observed. Serum IGF-II levels were elevated as a result of big IGF-II production. Taken together, these results indicated that hypoglycemia in this patient was associated with the production of big IGF-II by the MFH. The most effective therapeutic modality in patients with non-islet cell tumor hypoglycemia is resection of the tumor. In our case, as complete resection was impossible, dexamethasone and glucagon were administered and proved to be effective for preventing hypoglycemia.