The mechanism of the hypotensive effect during beta-adrenergic blockade in hypertension was studied in 38 patients with renal or essential hypertension using the new cardioselective beta blocker, Tenormin. During 5 weeks hospitalization the patients received first a placebo for 5 to 12 days, then a 75 mg. dose of Tenormin was given daily for 1 week, and thereafter the dose was doubled weekly as necessary up to 600 mg. daily. The blood pressure decreased from 180 +/- 26.2/118. "/- 13.6 mm. Hg on placebo to 151 +/-25.5/96 +/-13.8 mm. Hg during the final hospitalization period on Tenormin (600 mg. daily). Six patients developed fluid retention and as this occurred blood pressure control was lost. A subsequent follow-up on an outpatient basis of 15 of the patients showed that when the active drug was replaced by a placebo blood pressure rose again, confirming that the initial fall in blood pressure was a genuine effect. Multistage bicycle ergometer exercise tests were performed at weekly intervals to test the degree of beta blockade and indicated that this was nearly complete when a dose of 600 mg. per day was used. A significant correlation between the hypotensive effect and the degree of beta blockade, assessed by exercise tachycardia, was observed. A slight but statistically significant decrease (26 per cent) was observed in the plasma renin concentration, measured recumbent in the morning. This decrease was, however, not correlated with the hypotensive effect of the drug. Although the cardiac output decreased significantly (from 5.5 +/-1.7 to 4.3 +/- 1.1 L per minute, p less than 0.001), no correlation was found in individual patients between the cardiac output and the blood pressure decrease. On the other hand, for the total group of catheterized patients (n = 28) the calculated total peripheral resistance did not change significantly. Yet a significant correlation was found between the changes in total resistance and the hypotensive effect. This suggests that the reaction of the peripheral vessels rather than the cardiac output decrease determines whether the drug will produce a major decrease of blood pressure in patients with hypertension.