Metabolic alkalosis was induced in dogs by administering ethacrynic acid and sustained by feeding a chloride-deficient diet. At the height of the alkalosis extracellular fluid was expanded "isometrically," i.e., with an infusion that duplicated plasma sodium, chloride, and bicarbonate concentrations. Correction of metabolic alkalosis promptly followed such expansion and was attributed to the selective retention by the kidneys of chloride from the administered solution. Since plasma chloride concentration was not increased as an immediate consequence of the infusion, it is concluded that the change in renal tubular function that led to the selective retention of chloride must have been mediated by factors independent of filtrate chloride concentration.A decrease in circulating mineralocorticoid level, as a consequence of volume expansion, does not seem to account for this change in tubular function since identical studies in dogs receiving excessive amounts of 11-deoxycorticosterone acetate during the day of infusion yielded similar findings. Moreover, no other consequence of volume expansion appears to be sufficient to cause this change in tubular function in the absence of metabolic alkalosis; when the alkalosis was corrected with hydrochloric acid before infusion, isometric expansion of extracellular volume did not induce selective chloride retention. We suggest that isometric expansion during metabolic alkalosis causes a decrease in proximal sodium reabsorption that relinquishes filtrate to a more distal site in the nephron and that this site may retain chloride preferentially when hypochloremia or chloride deficiency is present.