Background: Sodium retention and volume expansion, mediated in part by aldosterone, are prominent features in low-renin hypertension. Agents that block aldosterone at its receptor sites, therefore, should have significant clinical benefit in patients with low-renin hypertension. Methods: This 16-week, multicenter, double-blind, active-controlled, parallel-group, titration-to-effect trial compared the blood pressure and neurohumoral responses of the selective aldosterone blocker eplerenone (100-200 mg/d; n = 86) with those of the angiotensin receptor blocker losartan (50-100 mg/d; n = 82) in patients with low-renin hypertension (active renin ≤25 pg/mL [≤42.5 mU/L]). Patients with diastolic blood pressure ≥90 mm Hg after 8 weeks of monotherapy received add-on therapy with hydrochlorothiazide 12.5 to 25 mg daily. Results: After 8 weeks of therapy, eplerenone reduced blood pressure to a greater extent than losartan (systolic blood pressure -15.8 vs -10.1 mm Hg, P = .017; diastolic blood pressure -9.3 vs -6.7 mm Hg, P = .05). After 16 weeks of therapy, significantly fewer eplerenone-treated patients (32.5%) than losartan-treated patients (55.6%) required add-on hydrochlorothiazide as allowed per protocol for blood pressure control (P = .003). Eplerenone consistently reduced blood pressure regardless of baseline active plasma renin levels whereas losartan reduced blood pressure more effectively in patients with higher baseline active renin levels. There were no differences between treatments in adverse events (reported by 62.8% of eplerenone patients and by 72.0% of losartan patients). Conclusions: These data show that eplerenone was more effective than losartan in reducing blood pressure in patients with low-renin hypertension. Further studies evaluating the efficacy of eplerenone in difficult-to-treat or resistant hypertension are needed.