In 50 patients with essential hypertension treated with chlorthalidone, 100 mg daily for 6 weeks, treatment responders (fall in mean pressure, greater than or equal to 10%) and nonresponders experienced similar weight and electrolyte changes. Although induced increments and post-treatment values of plasma renin were higher in nonresponders than responders, there was a far more striking difference in aldosterone reactivity. Aldosterone excretion rose by less than 10% in the responders but almost doubled in the nonresponders. Again, within the normal renin subgroup alone (n = 28), nonresponders exhibited control renin values and treatment-induced changes in plasma renin closely similar to those in responders, but experienced a significantly greater increase in aldosterone excretion. Possibly this increase in aldosterone produced subtle volume retention or a direct pressor effect in nonresponding patients. Although changes in aldosterone and in renin correlated with each other in both responders and nonresponders, the slopes of the regression lines in the two groups differed significantly. Thus, cofactors governing sensitivity of the aldosterone response to renin stimulation ultimately may determine the antihypertensive effectiveness of diuretics.