We report the case of a patient who presented with hypoglycemia associated with a giant breast mass and presence of serum high-molecular-weight insulin-like growth factor II (big IGF-II). In July 2005, a 49-year-old woman was admitted because of delirium, transient loss of consciousness, and a giant mass of about 28 cm in diameter on the right breast. She had noticed the mass for more than 2 years, but had refused medical attention at that time. A blood examination indicated hypoglycemia (21 mg/dl) and decreased levels of endogenous insulin. Furthermore, a western blot analysis revealed that big IGF-II (20 kDa) was the predominant serum IGF-II peptide (mature IGF-II is 7.5 kDa). Because we suspected that the big IGF-II was produced by the breast tumor and was likely the cause of the hypoglycemia, a mastectomy was performed. A histological examination determined that the mass was a benign phyllodes tumor. After surgery, the hypoglycemia resolved, and endogenous insulin levels improved. We suspected that the patient had non-islet cell tumor hypoglycemia (NICTH), but the behavioral symptoms of the hypoglycemia caused by NICTH were similar to some mental diseases, which made diagnosis based on the behavior alone difficult. We suggest that co-occurrence of symptoms such as recent appearance of mental disease-like behavior, hypoglycemia, and giant breast tumor may help diagnose NICTH caused by big IGF-II.