Several studies have shown that long-term therapy with angiotensin-converting enzyme inhibitors may reduce urinary protein excretion and decrease the rate of progression of renal disease in patients with insulin-dependent diabetes mellitus more effectively than conventional antihypertensive drugs. Only few studies, however, have been performed in patients with non-insulin-dependent diabetes mellitus (N1DDM). To compare the effects of captopril with more conventional drugs on proteinuria and progression of renal disease, we conducted a prospective, 18-month study in 42 proteinuric ( > 500 mg/day) NIDDM and, for comparison, in 31 nondiabetic patients with a variety of renal diseases (NDRD). Twenty-four NIDDM patients were treated with captopril and 18 with conventional drugs. Eighteen NDRD patients received captopril, and 13 received conventional drugs. Baseline proteinuria and glomerular filtration rate (GFR) were not different among groups. The blood pressure decreased equally in all group of patients, irrespective of whether they received captopril or conventional drugs. Urinary protein excretion, however, decreased significantly only in NIDDM and NDRD patients treated with captopril. The GFR decreased only in patients treated with conventional drugs, but not in those treated with captopril. The rate of decline in GFR in NIDDM patients treated with captopril was significantly lower than in patients treated with conventional drugs. However, in NDRD patients treated with captopril, the rate of decline in GFR was not different from that in patients treated with conventional drugs. The reduction of urinary protein excretion was poorly correlated with changes in blood pressure or with changes in renal function and renal hemodynamics. Serum potassium increased significantly in patients treated with captopril. These results have shown that in patients with NIDDM and NDRD long-term therapy with captopril may reduce urinary protein excretion and retard the progression of renal disease more effectively than conventional antihypertensive therapy.