The effects of oral carbohydrate on modulating counterregulatory responses in humans remain undecided. This study's specific aim was to determine the effects of oral carbohydrate on autonomic nervous system (ANS) and neuroendocrine responses during hyperinsulinemic hypoglycemia and euglycemia. Nineteen healthy volunteers were studied during paired, single blind experiments. Nine subjects underwent two step glucose clamps consisting of 60 min of euglycemia (5.0 mmol•l^-1) followed by either 15 gm of oral carbohydrate (cal) as orange juice or a non-caloric control (nocal) and subsequent 90 min of clamped hypoglycemia (2.9 mmol•l^-1). Ten other subjects underwent two randomized 150 min hyperinsulinemic-euglycemic clamps with cal or nocal control administered at 60 min. Oral carbohydrate initially blunted (p<0.05) epinephrine, norepinephrine, cortisol, glucagon, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom and systolic blood pressure responses during hypoglycemia. However, by the end of 90 min of hypoglycemia plasma epinephrine and norepinephrine responses had rebounded and were increased (p<0.05) as compared to control. MSNA and cortisol levels remained suppressed during hypoglycemia (p<0.05) after cal whereas pancreatic polypeptide, glucagon, symptom and blood pressure responses increased similar to control following initial suppression. Oral carbohydrate had no effects on neuroendocrine or ANS responses during hyperinsulinemic euglycemia. These results demonstrate that oral carbohydrate can have differential effects on the time course of ANS and neuroendocrine responses during hypoglycemia. We conclude that gastro-splanchnic-portal sensing of an amount carbohydrate recommended for use in clinical practice for correction of hypoglycemia can have widespread and significant effects on CNS mediated counterregulatory responses in healthy man.