Abstract--Previous studies suggest that the 2-adrenoceptor functions abnormally in patients with postural tachycardia syndrome (POTS) and may contribute to their altered hemodynamic profile. To test the hypothesis that the 2-adrenoceptor response is decreased in POTS, we studied: (1) the arterial vasodilation response to the agonist, isoproterenol, and (2) the distribution of common polymorphisms (codons 16 and 27) of the gene coding the receptor (₂-AR) in a large population with POTS. We measured plasma catecholamines and monitored hemodynamics and changes in forearm and leg blood flow to incremental doses of intraarterial isoproterenol in 9 patients with POTS compared with 8 healthy subjects. For polymorphism assessment we collected DNA from 57 patients with POTS and compared with 67 age-sex matched healthy subjects. Circulating catecholamines were significantly higher in POTS subjects compared with controls. Intrabrachial and intrafemoral isoproterenol infusion elicited a dose-dependent increase in blood flow. In healthy subjects, blood flow increased (mean±SEM) 400±70% in the forearm and 170±40% in the leg, but only 280±60% in forearms and 120±20% in legs of patients with POTS (ANOVA for both P<0.001). The genotype and allele distributions for codons 16 and 27 ₂-AR variants were not different in the 2 groups. However, the blood pressure and plasma norepinephrine levels diverged in patients according to their genotype. Patients with Gly16Gly and patients with Glu27Glu had lower plasma catecholamines and higher supine and upright blood pressure, compared with other genotypes. Therefore, both decreased 2-adrenoceptor-related vasodilation and ₂-AR polymorphisms may contribute to the hemodynamic diversity of patients with POTS.