Background- Stopping the detrimental effects of the renin- angiotensin systemat the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results- The study was a randomized, multicenter, double- blind, placebo- controlled, active- comparator 8- week trial in patients with mild- to- moderate hypertension(mean sitting diastolic blood pressure ≥ 95 and< 110mm Hg). After a 2- week, single- blind placebo run- in, 652 patients were randomized to receive double- blind treatment with oncedaily oral doses of aliskiren(150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure(SBP)(P< 0.001 versus placebo for both variables). The least- squares mean reductions in trough DBP were 9.3± 0.8, 11.8± 0.8, and 11.5± 0.8 mm Hg, respectively, versus 6.3± 0.8 mm Hg for placebo, and the least- squares mean reductions in trough SBP were 11.4± 1.3, 15.8± 1.2, and 15.7± 1.2 mm Hg, respectively, versus 5.3± 1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg(8.9± 0.7 and 12.5± 1.2 mmHg, least- squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg(P< 0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. Conclusions- Once- daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild- to- moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure. Background- Stopping the detrimental effects of the renin- angiotensin systemat the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results- The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8- week trial in patients with mild- to moderate hypertension (mean sitting diastolic blood pressure ≧ 95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double- blind treatment with onailyaily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, (P <0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3 ± 0.8, 11.8 ± 0 .8, and 11.5 ± 0.8 mm Hg, respectively, versus 6.3 ± 0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4 ± 1.3, 15.8 ± 1.2, and 15.7 ± 1.2 mm Hg, respectively, versus 5.3 ± 1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9 ± 0.7 and 12.5 ± 1.2 mmHg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups Conclusions- Once- daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild- to moderate hypertension. Aliskiren 150 mg is as effective as irbesa rtan 150 mgin lowering blood pressure.