Ethacrynic acid, a new diuretic, was administered on 137 separate occasions to 38 patients with refractory edema, usually orally at a dose of 1-16 mg/kg/6 hours. Patients with severe renal failure (BUN over 100 mg%), nephrotic syndrome, idiopathic orthostatic edema, acute oliguric renal ischemia and with hepatic or cardiac failure which failed to respond to diuretic therapy including mercurials were studied. Ethacrynic acid caused marked natriuresis and chloruresis, a diuresis of as high as 15% of the glomerular filtration rate and an increased osmolar clearance. To a lesser extent kaliuresis occurred and the increment in bicarbonate excretion was minimal. The percent of filtered Na excreted rose consistent with tubular blockade. Natriuresis and diuresis occurred despite adverse chemical changes such as hypoproteinemia, hyponatremia, hypochloremia, hypokalemia and alkalosis. The saluresis was a function of the glomerular filtrations rate and increased as the dose was raised to above 4 mg/kg/6 hours. Ethacrynic acid was surprisingly effective at low filtration rates, particularly when high doses were used. Continued administration tended to cause hypokalemic hypo [long dash]chloremic alkalosis, but diuresis continued nevertheless. When salt depletion occurred with a resultant fall in glomerular filtration rate diuresis diminished but did not cease, suggesting that patients will have to be monitored carefully to avoid severe volume depletion. The combination of ethacrynic acid and chlorothiazide was additive suggesting different sites of action. Uric acid clearance was depressed by ethacrynic acid. In patients with dilutional hyponatremia, free water clearance increased suggesting proximal reabsorptive blockade allowing delivery of Na to the diluting mechanism. In patients who were kaliuretic, potassium excretion usually increased suggesting increased delivery of Na to the exchange mechanism. This was blocked by spiro-nolactone. Diuresis was initiated in the ischemic kidney with oliguria after mannitol and hydration had failed. Significant toxicity may occur with high doses particularly in patients with reduced renal function.