This 52‐week, randomized, open‐label study evaluated long‐term safety/tolerability of fixed‐dose combination azilsartan medoxomil/chlorthalidone (AZL‐M/CLD) vs fixed‐dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160–190 mm Hg). Initial AZL‐M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL‐M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment‐emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL‐M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL‐M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed‐dose combination AZL‐M/CLD showed an encouraging benefit‐risk profile when used per standard clinical practice in a titrate‐to‐target strategy.