Since 1970, 197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantibodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe and the United States. High levels of the extractable native human insulin and of the characteristic insulin autoantibodies in the sera of the IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan.