Plasma levels and diuretic response were determined in seven healthy subjects and six patients with severe nephrotic syndrome (NS) after 40 mg furosemide (Fu). Mean apparent volume of distribution and distribution volume at steady state of the groups did not differ. Total Fu clearance was higher in NS (251 +/- 54 ml/min) that in healthy subjects (174 +/- 32 ml/min) (P less than 0.01), a difference that correlated with the nonrenal clearance of 56 +/- 28 ml/min in healthy subjects and 154 +/- 45 ml/min in patients with NS (P less than 0.001). Normal beta-elimination half-life of 51 +/- 7.7 min was 37 +/- 6.2 min (P less than 0.001) in NS. Mean normal Fu protein binding pf 98.6 fell to 97.2%, with decreasing plasma albumin levels. After 40 mg IV Fu, sodium and volume excretion decreased in NS (P less than 0.001 and P less than 0.005). In patients Na+/Fu excretion rate ratios showed "tubular resistance" to Fu over the time when large amounts of Fu were excreted. The reduced diuretic response to Fu in NS is taken to be mainly a consequence of its impaired renal excretion.