Abstract-Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure Յ119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (PϽ0.001). Changes in clinic systolic blood pressure (meanϮSE) were Ϫ42.5Ϯ0. 1 Therefore, there is a need for more effective antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products.Azilsartan medoxomil is a newly approved, effective, long-acting angiotensin II receptor blocker (ARB). It is a prodrug that is quickly hydrolyzed to the active moiety azilsartan, a potent and selective ARB with estimated bioavailability of 60% and elimination half-life of 12 hours.2 At its maximal dose, azilsartan medoxomil has superior efficacy compared with both olmesartan and valsartan at their maximum, approved doses, without increasing adverse events. [3][4][5] Chlorthalidone is a potent, long-acting thiazide-like diuretic that has a strong evidence base supporting cardiovascular benefit from randomized, controlled clinical trials. [6][7][8][9][10][11][12] It is also more effective in lowering BP than the more commonly used thiazide diuretic, hydrochlorothiazide.13 Therefore, combinations of azilsartan medoxomil and chlorthalidone are being developed as an effective 2-drug FDC.The present multicenter study is a large, forced-titration, active-comparator study of an ARB-chlorthalidone combination. We compared the antihypertensive efficacy, safety, and tolerability of azilsartan medoxomil plus chlorthalidone with