Intrarenal sodium handling was studied in 8 patients with essential hypertension before spironolactone treatment (200 mg/day), on the 4th day of treatment, and after 3 months of treatment. The results were compared with similar studies with chlorthalidone (50 mg/day). Renal sodium handling was assessed by simultaneous determination of the glomerular filtration rate, sodium, and potassium excretion, and maximal free-water clearance (CH<sub>2</sub>O). We took CH<sub>2</sub>O as an index of’distal’ sodium chloride reabsorption from which the proximal sodium reabsorption was calculated. During the first days of spironolactone treatment a natriuresis and increase in urinary flow rate was found. It resulted in a decrease of the extracellular fluid volume amounting to 0.9 liters and a 2.5-fold increase in the plasma renin activity. Potassium excretion showed a small but significant rise. After 3 months, virtually the same degree of volume depletion was found, which was comparable to that obtained after 3 months of chlorthalidone treatment. CH<sub>2</sub>O, as a fraction of glomerular filtration rate, decreased by 24% both after 3 days and 3 months, whereas proximal sodium reabsorption increased from 87.8 to 90.4% of the filtered load. CH<sub>2</sub>O, corrected for the ‘distal’ delivery of sodium, decreased from 85.3 to 80.7%. These changes were nearly the same as those found after 3 months of chlorthalidone treatment. It is concluded from these calculated values that spironolactone inhibits sodium chloride reabsorption in the diluting segment of the nephron and that the resulting increase in sodium delivery or urinary flow to the potassium excretory site partly counteracts the blocking effect of spironolactone on this part of the nephron, thus increasing potassium excretion during the acute administration of this drug.