We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure > or =90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92+/-15 pg/mL) and plasma renin activity (0.3+/-0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177 +/- 6/108 +/- 2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36+/-7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.