We herein report the case of a 57-year-old man with hyperglycemic hyperosmolar syndrome resulting in hemolytic anemia, who was diagnosed with hereditary spherocytosis during treatment. He was referred to our hospital with disturbance of consciousness. His plasma glucose concentration was very high (1617 mg/dL) with an HbA1c concentration of 12.4 %, suggesting hyperglycemic hyperosmolar syndrome. He was therefore admitted to our hospital. His plasma glucose concentration was gradually decreased with fluid replacement and continuous intravenous insulin infusion. As his dehydration and hyperglycemia improved, his hemoglobin level showed an extreme decrease, declining to 6 g/dL, and blood transfusion was performed. He was diagnosed with hemolytic anemia because his indirect bilirubin level was high, and his haptoglobin was very low with negative direct and indirect Coombs tests and no hemorrhagic lesion. Microscopy revealed some spherocytes in his peripheral blood. He had a swollen spleen with a family history of hemolytic anemia. A red blood cell resistance test showed that his red blood cells were weaker than normal. Thus, he was diagnosed with hereditary spherocytosis. Hemolytic anemia rarely occurs in patients with hereditary spherocytosis when they are in a normal condition. The drastic change of osmolarity induced by treatment for hyperglycemic hyperosmolar syndrome was suggested to have induced the hemolyzation of the weak membrane of the red blood cells in the present case.