To clarify why diuretic therapy raises plasma urea in patients with chronic renal failure, three groups of uraemic subjects were treated with frusemide for 6 days. In group 1 (n = 9), frusemide significantly decreased body weight and increased average plasma urea from 18.7 mmol/l to 28.8 mmol/l (P less than 0.001). this rise in plasma urea was secondary to reduced urea excretion, which occurred in spite of an increase in urea filtration. In group 2 (n = 7), frusemide was associated with salt replacement, in order to prevent salt depletion; in these patients neither reduction in urea excretion nor increase in plasma urea occurred. In group 3 (n = 10), the marked diuretic-induced fall in urea clearance was found to be independent of enhanced proximal tubular reabsorption (measured in water diuresis). These results show that the rise in plasma urea is due to increased tubular reabsorption of urea, presumably in the distal part of the nephron, secondary to extracellular fluid (ECF) volume depletion.