We sought to elucidate further the neurologic defect of idiopathic orthostatic hypotension, which appears to represent two distinct clinical entities. While recumbent, patients with multiple Central-nervous-system defects, as well as peripheral autonomic nervous dysfunction, have normal plasma levels of norepinephrine that fail to increase normally after standing or exertion (P<0.001 by t-test as compared to controls). While recumbent, patients with peripheral autonomic insufficiency without signs of Central-nervous-system defects have low levels of plasma norepinephrine (P<0.001) that also fail to increase normally after standing or exercising (P<0.001). Both groups have low levels of plasma dopamine-β-hydroxylase (P<0.02). These findings are consistent with other pathological and pharmacologic observations suggesting that patients with Central-nervous-system disease are unable to activate appropriately an otherwise intact sympathetic nervous system, whereas in patients without signs of Central-nervous-system disease the deficit affects peripheral sympathetic nerves. (N Engl J Med 296:293–297, 1977)