Renal hemodynamics and tubular solute and water handling were evaluated in normal subjects during water diuresis, before and after the acute administration of captopril, ibuprofen, or the combination of both drugs. The glomerular filtration increased after captopril administration but did not change after ibuprofen alone or in combination with captopril. Renal plasma flow increased with captopril alone and captopril plus ibuprofen but did not change after ibuprofen alone. Urine volume and Na excretion increased with captopril and decreased after ibuprofen; coadministration of ibuprofen attenuated the tubular effects produced by captopril alone. FELi, fractional delivery of solute to the distal nephron, and FELi-FENa, fractional distal reabsorption of solute, both significantly increased after captopril and decreased after ibuprofen but did not change with the combined regimen. (FELi-FENa)/FELi, fractional reabsorption of distally delivered Na, significantly decreased after captopril and increased after ibuprofen but remained unchanged after captopril plus ibuprofen. Thus captopril and ibuprofen have opposing effects on tubular Na and water handling, which are attenuated by the addition of the other drug. This interaction may have clinical relevance in patients with heart failure or hypertension, in whom captopril is used to enhance Na and water diuresis.