Summary:The effect on blood pressure of high (400 mg/day‐S400) and moderate dose (200 mg/day‐S200) spironolactone and chlorthalidone (100 mg/day—C100), given in a random double‐blind manner was related to plasma renin activity and plasma volume in 38 essential hypertensives.The fall in pressure from a control of 154/103 mm Hg was essentially the same after four weeks of each drug—S400 ABP 24/13 mm, S200 18/9 mm, C100 17/12 mm (allP<0–001).Twelve of 37 patients (32%) had low initial renin, but this appeared as responsive to the chlorthalidone stimulus as that of the normal renin group. The anti‐hypertensive effect of all regimens was unrelated to plasma renin activity.Plasma volume was significantly lowered at the end of each treatment period, but the decline could not be correlated with blood pressure effects. Patients with initially low plasma volume were more likely to respond to S400 (r= 0.545,P<0.01), whereas the anti‐hypertensive effect of the S200 and C100 regimens was independent o