Background: Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. Duration of diabetes, blood pressure values, and metabolic status are the major determinants of the course of nephropathy, and microalbuminuria is the hallmark of its onset. Angiotensin-converting enzyme inhibitors offer important renoprotection to hypertensive and normotensive patients with insulin-dependent diabetes mellitus and non- insulin-dependent diabetes mellitus. Our study extends previous observations for duration and the effect of angiotensin converting enzyme inhibition on advanced nephropathy. Methods: Double-blinded (first phase) and open (second phase) randomized controlled study of 7 years. Ninety-four normotensive patients with non-insulin-dependent diabetes mellitus whose serum creatinine levels were lower than 123.76 μmol/L (1.4 mg/dL) and who had microalbuminuria (30 to 300 mg/24 h) were given enalapril maleate, 10 mg/d, or placebo, for 5 years. For 2 more years they were followed up openly and given the choice to receive enalapril or no treatment. Results: In the enalapril-treated patients, albuminuria remained stable for 7 years. An increase from (mean ± SD) 123 ± 58 to 310 ± 167 mg/24 h occurred in the untreated group after 5 years, and a further increase to (mean ± SD) 393 ± 223 mg/24 h occurred after 7 years. Reciprocal creatinine was unchanged in treated patients for 7 years; in the untreated patients, the mean decline was 13% at 5 years and 16% at 7 years. Treatment with enalapril resulted in an absolute risk reduction of 42% for nephropathy to develop during 7 years (95% confidence interval, 15% to 69%; P<.001, Student's t test). Glycosylated hemoglobin and body mass index remained unchanged. Conclusions: Angiotensin- converting enzyme inhibition offers long-term protection against the development of nephropathy in normotensive patients with non-insulin- dependent diabetes mellitus who have microalbuminuria, and it stabilizes renal function in previously untreated patients with impaired renal function. Discontinuation of treatment results in renewed progression of nephropathy.