Azilsartan medoxomil (AZL-M) is a unique angiotensin II receptor blocker (ARB) under development for the treatment of hypertension. To compare this ARB with another in the class, the authors studied the effects of AZL-M and valsartan (VAL) in 984 patients with primary hypertension in a randomized, double-blind, multicenter study using ambulatory and clinic blood pressure (BP) measurements. The primary end point was change from baseline in 24-hour mean ambulatory systolic BP following 24 weeks of treatment. Hierarchical analysis testing for noninferiority was followed by superiority testing of AZL-M (80 mg then 40 mg) vs VAL. The mean age of participants was 58 years, 52% were men, and 15% were black. Baseline 24-hour mean systolic BP was similar (approximately 145.6 mm Hg) in each group. AZL-M 40 mg and 80 mg lowered 24-hour mean systolic BP (-14.9 mm Hg and -15.3 mm Hg, respectively) more than VAL 320 mg (-11.3 mm Hg; P<.001 for 40-mg and 80-mg comparisons vs VAL). Clinic systolic BP reductions were consistent with the ambulatory results (-14.9 mm Hg for AZL-M 40 mg and -16.9 mm Hg for AZL-M 80 mg vs -11.6 mm Hg for VAL; P=.015 and P<.001, respectively). The reductions in 24-hour mean and clinic diastolic BPs were also greater with both doses of AZL-M than with VAL (P≤.001 for all comparisons). Small, reversible changes in serum creatinine occurred more often with AZL-M than with VAL; otherwise, safety and tolerability parameters were similar among the three groups. These data demonstrate that AZL-M across the effective dose range had superior efficacy to VAL at its maximal recommended dose without any meaningful increase in adverse events. These findings suggest that AZL-M could provide higher rates of hypertension control compared with other ARBs in the class. © 2011 Wiley Periodicals, Inc.