Renin angiotensin system parameters and blood pressure (B.P.) were followed monthly in patients with essential hypertension on metolazone, 5 mg daily for three months and with added propranolol, 40 to 160 mg, for the subsequent three months. On metolazone alone at three months, sitting B.P. declined from 166/108 +/- 14/11 mm Hg to 145/98 +/- 14/9 mm Hg (P less than 0.005). Plasma renin activity (PRA) increased from 3.9 +/- ng/ml/hr to 10.4 +/- 8.6 ng/ml/hr (P less than 0.005); plasma angiotensinogen did not change. Venous blood angiotensin I and II levels (pg/ml) rose initially but returned toward control values. A significant decline in plasma renin substrate reactivity (PRSr) in index occurred. Propranolol addition caused further lowering of only systolic B.P. and predominantly in the standing position, more marked at one month (40 mg) than at three months (160 mg). No significant further changes were observed in any of the measured parameters of renin angiotensin system, except for a rise in PRSr index concomitant with B.P. elevation at three months. Metolazone-induced changes in B.P. showed significant correlations at three months with changes in PRSr index. It is concluded that during chronic metolazone administration, the overall activity of the renin angiotensin system was diminished or unchanged. Propranolol did not inhibit metolazone stimulated PRA but did cause further decline in B.P. in the first two months, unrelated to renin angiotensin system.