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 less than 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 less than 0.001) that also fail to increase normally after standing or exercising (P less than 0.001). Both groups have low levels of plasma dopamine-beta-hydroxylase (P less than 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.