The influence of angiotensin-converting enzyme (ACE) inhibition on renal tubular function in progressive chronic nephropathy was investigated in 69 patients by the lithium clearance (C(Li)) method. Studies were done repeatedly for up to 2 years during a controlled trial on the effect of enalapril on progression of renal failure. The pattern of proteinuria was followed over the first 9 months. At baseline, the glomerular filtration rate (GFR) was 5 to 68 mL/min. Absolute proximal tubular reabsorption rate of fluid (APR), estimated as the difference between GFR and C(Li), was 1 to 54 mL/min. Calculated fractional proximal reabsorption (FPR) was moderately subnormal. During the study, GFR decreased and sodium clearance was unchanged; fractional excretion of sodium therefore increased. In the group of patients randomized to treatment with enalapril (n = 34), GFR at 1 month was 83% (P < 0.001) and C(Li) was 88% (P < 0.01) of the baseline values, APR and FPR had not changed significantly, and potassium clearance was significantly decreased. Through the rest of the study period, APR remained nearly unchanged and FPR even increased in the enalapril group. In the group of patients randomized to treatment with conventional antihypertensive drugs (n = 35), C(Li) was unchanged until severe reduction in GFR, APR and FPR decreased gradually, and potassium clearance was almost unchanged. These differences in tubular function between the two treatment regimens were significant (P < 0.05). An unchanged or increased APR in either treatment regimen was associated with a long-term slower progression of renal failure. Over 9 months, the 24-hour fractional clearance of albumin decreased in the ACE inhibitor group (P < 0.01), whereas the clearances of immunoglobulin G and retinol-binding protein were unchanged in this group. In the conventional group, the fractional clearances of these three plasma proteins all increased. It is concluded that in progressive chronic nephropathy ACE-inhibitor treatment was associated with different adaptive tubular changes in the handling of sodium, water, and protein compared with conventional antihypertensive therapy. During ACE inhibition, the reabsorptive capacity of the proximal tubule appeared to be better preserved, which might be of importance for the beneficial effect of this treatment in chronic renal disease.