Vanadate, furosemide, chlorothiazide, acetazolamide, and amiloride were infused concomitantly into conscious rats to determine the extent to which renal sodium reabsorption can be inhibited. The animals were maintained in exact fluid balance despite exorbitant urine flow rates by intravenous infusion of an isotonic salt solution sufficient to keep body weight constant. In maximally effective doses vanadate, furosemide, chlorothiazide, acetazolamide, and amiloride increased sodium excretion to an amount equal to 69% of the filtered load. Together with isotonic extracellular fluid expansion equal to 7% of body weight, these pharmacologic agents increased sodium excretion to an amount equal to 83.7% of the filtered load, a level of sustained sodium excretion that has not been reported previously in mammals. These studies demonstrate that tubular sodium and water reabsorption can be profoundly inhibited in vivo by drugs that diminish sodium and water transport in proximal as well as in distal tubules.