Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-¹³C]glucose infusion to increase plasma ¹³C enrichment. In vivo brain ¹³C magnetic resonance spectroscopy was used to measure the time course of ¹³C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (V_TCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the V_TCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the V_TCA was inversely related to the HbA_1C and was, under hypoglycemic conditions, approximately 45% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes.