The relative contributions of the sympathetic nervous system and the adrenal medullae, the two components of the sympathoadrenal system, to the manifestations of hypoglycemia are largely unknown. We tested the hypothesis that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural activation. To do so, we quantitated neurogenic symptoms, as well as norepinephrine (NE) kinetics and selected hemodynamic changes, during hyperinsulinemic euglycemic and stepped hypoglycemic clamps in 15 healthy control subjects (Controls) and four bilaterally adrenalectomized patients (ADX). Plasma epinephrine responses to hypoglycemia were virtually absent in ADX, as expected. Neurogenic symptom scores increased to higher values during the hypoglycemic compared with the euglycemic clamps in both Controls (P < 0.0001) (e.g., final scores of 7.8 +/- 1.2 vs. 3.0 +/- 0.7) and ADX (P < 0.0001) (e.g., final scores of 10.8 +/- 4.1 vs. 2.5 +/- 1.0). Plasma NE concentrations (P < 0.0001) and systemic NE spillover (P = 0.0007) increased during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. Similarly, heart rate increased (P = 0.0104), diastolic blood pressure decreased (P = 0.0003), and forearm blood flow increased (P < 0.0001) during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. These data indicate that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural, rather than adrenomedullary, activation. They also suggest that the plasma NE and hemodynamic responses to hypoglycemia are largely the result of adrenomedullary, rather that sympathetic neural, activation.