To determine whether the alpha-adrenergic antagonist phenoxybenzamine would alter cardiovascular or plasma catecholamine response to the alpha-adrenergic agonist clonidine, six patients with pheochromocytomas and eight with labile hypertension were studied. Clonidine, 0.3 mg, was given with and without 48 hr pretreatment with 30 mg/day phenoxybenzamine. The response to 10 mg diazepam was also observed in seven of the subjects who had labile hypertension. In the hypertensive patients, clonidine alone induced a fall in supine blood pressure from 137 +/- 21/91 +/- 14 to 109 +/- 18/76 +/- 17 mm Hg and, with phenoxybenzamine, clonidine reduced blood pressure from 141 +/- 22/89 +/- 10 to 107 +/- 21/72 +/- 11 mm Hg. Plasma norepinephrine fell from 179 +/- 60 to 107 +/- 79 pg/ml without phenoxybenzamine and from 229 +/- 159 to 95 +/- 46 pg/ml with phenoxybenzamine in hypertensive subjects. Responses with phenoxybenzamine did not differ from those without phenoxybenzamine and diazepam induced no cardiovascular or plasma catecholamine changes. Clonidine did not lower plasma catecholamines in patients with a pheochromocytoma in the presence or in the absence of phenoxybenzamine. Blood pressure tended to decline after clonidine in pheochromocytoma patients not taking phenoxybenzamine, but it was not reduced by clonidine when these patients were taking phenoxybenzamine. Phenoxybenzamine does not inhibit reduction in blood pressure and plasma catecholamines induced by clonidine in patients with essential hypertension or interfere with the clonidine suppression test in patients with pheochromocytomas.