Ethacrynic acid, a chemically different diuretic, has been evaluated in 82 patients. The drug was remarkably potent when administered intravenously (0.5 to 1 mg./Kg.) or by mouth (doses to 50 mg. four times per day). It proved particularly effective in patients with refractory edema, and in edematous states accompanied by azotemia or electrolyte disturbances. Its natriuretic effects added to those of other diuretics and potentiation actually appeared to occur when it was combined with a carbonic-anhydrase inhibitor.Renal clearance data indicated that ethacrynic acid has a unique mode of action. There was little effect on glomerular filtration or renal plasma flow and its major action was to block sodium and chloride reabsorption probably in both proximal and distal portions of the renal tubules.Ion exchange mechanisms seemed little affected by the drug because it characteristically increased both hydrogen and potassium ion excretion. In general the degree of induced potassium loss correlated well with the rate of endogenous aldosterone secretion. Furthermore, ethacrynic acid did not cause potassium loss in one adrenalectomized subject nor in another subject pretreated with an aldosterone antagonist.Diuresis induced by ethacrynic acid was often accompanied by the development of systemic metabolic alkalosis. Factors in the development of this alkalosis were (1) urinary K+loss with hypokalemia, (2) urinary H+loss, and (3) in edematous patients the rapid large loss of relatively HCO3--free fluid from the extracellular fluid space. The systemic alkalosis was found to be accompanied by compensatory alveolar hypoventilation. These studies of the mechanisms of the alkalosis point to the occasional importance ofthe administration of chloride, of potassium, or of saline as corrective measures.Diuresis with ethacrynic acid, like other diuretic agents, produced marked increases in the rate of aldosterone secretion of normal subjects. More variable effects were observed in patients with heart disease, possibly because improvement in their circulatory status operated to lower hormone secretion activity.Ethacrynic acid had effects on urate excretion that resembled thiazide diuretics. Higher blood levels of intravenous administration were uricosuric. Lower blood levels of oral therapy caused renal urate retention and hyperuricemia.Most of the problems associated with the use of ethacrynic acid appeared to be related more to its pharmacologic potency than to any truly toxic effect. Because of this it is suggested that the sensitivity and response pattern of each patient be determined in stepwise fashion. In most patients with edema an intermittent dosage schedule provides a more efficient diuretic response and allows time intervals for correction of any electrolyte imbalance. If used with a thorough understanding of its pharmacologic effects ethacrynic acid promises to be a most useful agent in the therapy of patients with difficult or refractory edema.