We studied the efficacy of the ACE inhibitor lisinopril in treating overt proteinuria in comparison with the NSAID indomethacin, and evaluated some of the conditions that could influence this antiproteinuric effect. In 12 patients with a proteinuria varying from 3.2 to 10.5 g/24 hr, a diastolic BP ranging from 64 to 105 mm Hg, and a GFR varying from 34 to 127 ml/min, the effect of different lisinopril doses and of changing dietary sodium intake was evaluated. Proteinuria fell by 27 +/- 20% from 6.1 +/- 2.1 to 4.5 +/- 1.9 g/24 hr on a low dose (median 5 mg/day) lisinopril and by 50 +/- 17% to 3.1 +/- 1.4 g/24 hr on a higher dose (median 10 mg/day), irrespective of initial proteinuria, BP, or GFR. This antiproteinuric effect was abolished by increasing salt intake from 50 to 200 mmol/day, and was recovered again by re-instituting the sodium restricted diet. The antiproteinuric effect of 10 mg/day lisinopril was comparable to the reduction in proteinuria (by 57 +/- 21% to 2.8 +/- 2.0 g/24 hr) on 150 mg/day indomethacin, while adverse effects were less and renal hemodynamic effects were more favorable during lisinopril. In some patients it took several weeks before the effect of the ACE inhibitor on proteinuria was stabilized. Thus, the antiproteinuric effect of the ACE inhibitor lisinopril appears to be dose and time related, and is strongly dependent on dietary sodium restriction, whereas it does not depend on initial proteinuria, BP, or GFR. The effect is comparable to that of indomethacin, while adverse effects are less.