Efficacy and safety of the direct renin inhibitor aliskiren was compared with ramipril for treatment of essential systolic hypertension in elderly patients. A 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study was performed in 901 patients (aliskiren, n=457; ramipril, n=444) > or =65 years of age with systolic blood pressure (SBP) > or =140 mm Hg. Aliskiren 150-300 mg per day or ramipril 5-10 mg per day for was administered for 12 weeks with optional add-on therapy of hydrochlorothiazide (12.5-25 mg per day) at week 12 and amlodipine (5-10 mg per day) at week 22. The primary end point was non-inferiority of aliskiren vs ramipril monotherapy for change from baseline in mean sitting SBP (msSBP) at week 12. Decreases from baseline msSBP and mean sitting diastolic BP with aliskiren monotherapy (-14.0 and -5.1 mm Hg, respectively) were non-inferior (P<0.001 for both values) and superior to ramipril monotherapy (-11.6, -3.6 mm Hg; P=0.02, P<0.01, respectively). More patients achieved BP control with aliskiren (42%) than ramipril (33%; P<0.01). At week 36, fewer patients receiving aliskiren-based therapy required add-on treatment with hydrochlorothiazide or amlodipine (P=0.01 and 0.048, respectively). Tolerability was similar, but more patients receiving ramipril reported cough (P<0.001). In elderly patients with systolic hypertension, aliskiren proved to be more effective and better overall anti-hypertensive therapy compared to ramipril.