The antihypertensive effects of atenolol and hydrochlorothiazide were compared with placebo in a randomized, double-blind crossover study, with the blood pressure responses related to sympathetic nervous system activity. Twelve patients with essential hypertension were given atenolol (100 mg), hydrochlorothiazide (50 mg), and placebo as single daily doses, each for 6 weeks. Mean supine, standing, and post-exercise blood pressures (mm Hg) on atenolol (155/94, 152/95, 177/93, respectively) and hydrochlorothiazide (154/99, 150/103, 172/96) were lower (p less than 0.01) than corresponding placebo values (172/109, 166/113, 204/111) at 6 weeks. The role of the sympathetic nervous system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined. The supine plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each patient's "adrenergic status." The six "hyperadrenergic" patients with high resting norepinephrine values (mean, 302 pg/ml) exhibited a greater (p = 0.05) decrease in BP (-30/-20 mm Hg) on atenolol compared with the BP fall of -9/-11 mm Hg observed in the lower norepinephrine group (mean, 211 pg/ml). Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide. The "adrenergic status" of each patient as measured by the plasma norepinephrine concentration tended to be relatively constant regardless of therapy or the state of activity. In this study, atenolol was an effective antihypertensive agent comparable to hydrochlorothiazide in potency. Adrenergic status tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all treatment phases.