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Hypoglycemia due to non-islet cell tumor is usually associated with hypersecretion of big insulin-like growth factor II (IGF-II). This big IGF-II cannot form ternary IGF complex, and is biologically more active in peripheral tissue, inducing increased glucose utilization and hypoglycemia. A 57-year-old man developed severe hypoglycemia due to hepatocellular carcinoma. To control hypoglycemia, the patient required continuous glucose infusion. The circulating levels of cortisol and free T4 were in the normal range. The plasma levels of insulin, C-peptide, IGF-I, IGF binding protein-3 (IGFBP-3), and total IGF-II levels were decreased. Radioimmunoassay of IGF-II revealed that big IGF-II immunoreactivity markedly increased compared to that of normal control. In this patient, it was strongly suggested that big IGF-II might be a cause of severe intractable hypoglycemia.