In a double-blind crossover study in 10 salt-depleted nephrotic patients the reduction of proteinuria was significantly larger during indomethacin 50 mg three times daily than during naproxen 250 or 500 mg three times daily (72 vs. 44%, p less than 0.05; 77 vs. 46%, p less than 0.05, respectively). Both drugs induced similar reversible intrarenal hemodynamic changes, but indomethacin had more pronounced effects than naproxen. A common pathway, such as the reduction of the glomerular filtration rate and a reduction of the glomerular transcapillary hydraulic pressure, is likely to explain the observed phenomena and is most probably mediated by inhibition of intrarenal prostaglandin synthesis. If treatment with a nonsteroidal anti-inflammatory drug is considered in patients with the idiopathic nephrotic syndrome, indomethacin appears up to now the most effective agent in reducing urinary protein loss.