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Background-LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. Methods and Results-We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (nϭ92), 0.5 mg once daily (nϭ88), 1.0 mg once daily (nϭ86), and 0.5 mg twice daily (nϭ97); eplerenone 50 mg twice daily (nϭ84); or placebo (nϭ77) for 8 weeks. Adrenocorticotropic hormone (250 g IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-␤-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (Ϫ7.1 mm Hg; Pϭ0.0012) and eplerenone 50 mg twice daily (Ϫ7.9 mm Hg; PϽ0.0001) compared with placebo (Ϫ2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (PϽ0.005 or better) and eplerenone (PϽ0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (PϽ0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in Ϸ20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone. Conclusions-Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524.