We investigated the effects of varying salt intake on five factors that could affect sodium balance during furosemide (F) administration: the quantity of F reaching the renal tubules; the magnitude of the acute natriuresis; Na+ excretion in the period after the acute diuresis; diuretic tolerance; and changes in plasma aldosterone. Six normal subjects were given F (40 mg day-1) for 3 days after equilibration to Na+ intakes of 20 mmol day-1 (low salt, LS) and 270 mmol day-1 (high salt, HS). Salt intake did not modify F excretion. Salt restriction reduced the short-term natriuretic response to F, led to diuretic tolerance, and potentiated the F-induced rise in plasma aldosterone. There was a progressive diminution in the quantity of Na+ excreted per unit of F excreted during LS. In spite of this, cumulative Na+ balance was negative only during LS because of a compensatory increase in Na+ reabsorption in the period between diuretic doses. During HS, this compensation exactly matched the short-term loss of Na+ produced by F, leading to neutral Na+ balance. During LS, the acute natriuresis exceeded the daily Na+ intake, so that, despite the renal compensation, Na+ balance was negative. In conclusion, salt restriction impairs the short-term natriuretic response to F and leads to diuretic tolerance. However, homeostatic mechanisms activated by the diuretic can maintain Na+ balance even in subjects without a disease causing Na+ retention, unless dietary salt is restricted.