Brain damage due to severe hypoglycemia occurs in insulin treated people with diabetes. This study tests the hypothesis that chronic insulin therapy that normalizes elevated blood glucose in diabetic rats would be neuroprotective against brain damage induced by an acute episode of severe hypoglycemia. Male Sprague-Dawley rats were split into 3 groups, 1) control, non-diabetic, 2) STZ-diabetic, and 3) insulin treated STZ-diabetic. After 3 weeks of chronic treatment, unrestrained, awake rats underwent acute hyperinsulinemic/severe hypoglycemic (10-15 mg/dl) clamps for 1 hour. Rats were subsequently analyzed for brain damage and cognitive function. Severe hypoglycemia-induced 15-fold more neuronal damage in STZ diabetic rats as compared to non-diabetic rats. Chronic insulin treatment of diabetic rats, that nearly normalized glucose levels, markedly reduced neuronal damage induced by severe hypoglycemia. Fortunately, no cognitive defects associated with the hypoglycemia-induced brain damage were observed in any group. In conclusion, antecedent blood glucose control represents a major modifiable therapeutic intervention that can afford diabetic subjects neuroprotection against severe hypoglycemia-induced brain damage.