It is unknown if the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors reflects attenuation in the rate of progression of diabetic nephropathy. We report the results of a randomized, double-blind clinical trial designed to evaluate the longitudinal (18-month) effect of the ACE inhibitor, enalapril (5 to 40 mg/d), versus a placebo on 24-hour urinary protein excretion and on the rate of progression of renal disease in 33 patients with clinical diabetic nephropathy. Systemic blood pressure was controlled throughout the trial with conventional antihypertensive drugs. Glomerular filtration rate (GFR), determined by Tc99mDTPA renal clearance, and urinary protein excretion were monitored at 3-month intervals. Enalapril, in contrast to placebo therapy, was associated with an initial (40%) and sustained (33%) decrease in urinary protein excretion. Patients randomized to both enalapril or placebo experienced mean decreases in GFR, from 1.01 mL/s/1.73 m2 (61 mL/min/1.73 m2) to 0.85 mL/s/1.73 m2 (51 mL/min/1.73 m2), and from 1.06 mL/s/1.73 m2 (64 mL/min/1.73 m2) to 0.97 mL/s/1.73 m2 (58 mL/min/1.73 m2), respectively. Eleven of 18 patients (61%) randomized to enalapril, and 10 of 15 (66%) patients randomized to placebo, had a decrease in GFR; their rates of progression were -1.18 mL/min/1.73 m2/mo and -1.00 mL/min/1.73 m2/mo, respectively. In the absence of changes in blood pressure, the addition of an ACE inhibitor to patients with clinical diabetic nephropathy could not be shown to confer a unique renal protective effect. A prolonged decrease in 24-hour protein excretion could not be shown to predict attenuation in the progression of established clinical diabetic nephropathy.