Studies indicate that aldosterone and angiotensin II have independent etiologic roles in cardiovascular outcomes. This 12-month, double-blind, titration-to-effect study compared the efficacy and safety of eplerenone (EPL), a selective aldosterone blocker, and enalapril (ENAL), an ACE inhibitor, in the treatment of hypertension. Patients with mild-to-moderate hypertension (DBP ≥95 mmHg and <110 mmHg) were randomized to receive initially EPL 50 mg QD (n=253) or ENAL 10 mg QD (n=246). If DBP ≥90 mmHg at Weeks 4, 8, 12, 16, or 20, the dose of study medication was up-titrated incrementally to EPL 100 mg and 200 mg QD, or ENAL 20 mg and 40 mg QD. To examine whether treatment resulted in long-term alterations in the hypertensive disease state, all patients whose BP was controlled at Week 24 were down-titrated one dose level and followed monthly for an additional 6 months (study medication doses were re-up-titrated to Week 24 levels if the down-titration resulted in loss of BP control). At Week 24 and 12 months, changes in BP, RAAS hormone profile, UACR, laboratory tests, safety, and AEs were assessed. Blood pressures (SBP/DBP) were comparably reduced by both drugs at Week 24 (EPL -14.5/-11.2 mmHg, ENAL -12.7/-11.3 mmHg) and 12 months (EPL -16.5/-13.3 mmHg, ENAL -14.8/-14.1 mmHg). Similar percentages of patients in the EPL (46%) and ENAL (52%) groups continued to have BP controlled at 12 months with the down-titrated dose. In patients with elevated baseline microalbuminuria (UACR ≥30 mg/g), a significantly greater reduction in UACR was observed with EPL than ENAL (-61.5% vs -25.7%, P=0.01) at Week 24. Significantly greater proportions of ENAL patients experienced coughing (6.5% vs 2.4%, P=0.029), hyperglycemia (2.8% vs 0.0%, P=0.007), and UTI (2.8% vs 0.4%, P=0.035). In conclusion, selective aldosterone blockade with eplerenone was as effective as enalapril in controlling BP. Eplerenone-treated patients displayed a greater reduction in UACR, a prognostic predictor of end-organ damage, and had fewer adverse events.