Angiotensin-converting enzyme inhibitors delay progression of renal disease in different animal models of nephropathy. We tested this treatment modality in 70 hypertensive patients with severe renal disease of various etiologies. We report a double-blind study of the effect of 5 mg enalapril once daily compared with placebo in patients with nondiabetic severe chronic renal impairment (plasma creatinine 2.8 to 6.8 mg/dL; mean creatinine clearance 15 mL/min/1.73 m2) followed for up to 2 years. Efficacy parameters were the slopes of 51Cr-EDTA clearance, reciprocal of plasma creatinine, creatinine clearance, and the effect on urinary protein excretion. Thirty-one patients completed 2 years of treatment (12 in the enalapril group and 19 in the placebo group). Two patients died from nonrenal causes (one patient each in the enalapril and placebo groups), 16 patients commenced dialysis (seven in the enalapril group and nine in the placebo group), and eight patients were discontinued due to adverse events (five in the enalapril group and three in the placebo group). Eleven patients were discontinued because they were noncompliant, uncooperative, or moved (nine in the enalapril group and two in the placebo group). Two enalapril-treated patients were dropped from the study due to protocol deviations. Importantly, the statistical approach in this study evaluated all patients, regardless of the duration of treatment. A mixed-effects linear model and intention to treat analysis, taking into account the number of observations per patient, indicated that enalapril significantly reduced the rate of deterioration of renal disease: glomerular filtration rate (P = 0.038), reciprocal of plasma creatinine (P = 0.017), or creatinine clearance (P = 0.031). The renal protective effects of enalapril were shown to be in addition to its antihypertensive effect when blood pressure was held constant. Proteinuria was reduced by enalapril (P = 0.007) and was slightly increased in the placebo-treated patients (P = 0.051). The difference between these two groups was highly significant (P = 0.002). In conclusion, enalapril retarded the progression of chronic renal failure, as assessed by changes in glomerular filtration rate, creatinine clearance, and 1/plasma creatinine, and reduced proteinuria in patients with nondiabetic severe chronic renal insufficiency.