1. Neither the mechanism nor the therapeutic implications of the ability of ethacrynic acid to stimulate renal H + secretion has been fully explored. Acute studies were carried out in six normal volunteer subjects to determine whether or not the stimulation of H + excretion depended upon sodium chloride or volume depletion. 2. Depletion was either not corrected, or corrected by one of the following: oral water alone or sodium chloride solution (either 153 mmol/l or 513 mmol/l) intravenously to give zero or slightly positive balances of water, sodium chloride or both at all times. Urine was collected at 2 h intervals before and for 8 h after 100 mg of ethacrynic acid. Electrolytes, pH, total acid, osmolality and true creatinine were measured in each urine specimen and in the serum during the control period and 5·5 h after ethacrynic acid. 3. In all 14 experiments in six subjects, urinary pH was reduced to a mean value 4·78 ± se 0·08 within 2–8 h after ethacrynic acid irrespective of replacement therapy, indicating that the sodium chloride and volume depletions produced by ethacrynic acid were not essential to its effect on urinary pH. 4. Urinary pH correlated inversely ( r = −0·81) with the logarithm of the difference between rejected chloride and sodium per unit of rejected chloride, suggesting that the discrepancy between anion-cation reabsorption was intimately linked to generation of H + gradients, possibly by reducing chloride transport. 5. Three of the subjects were given amiloride (20 mg) with ethacrynic acid: both the pH reduction and the chloride/sodium differentials were abolished, probably by reduction of tubular sodium reabsorption. A specific but opposite effect of both agents on tubular H + transport cannot be excluded.