This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50-100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose-response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of -7.0 (-9.5 to -4.6)/-3.8 (-5.2 to -2.4) mmHg in the placebo group, and -10.7 (-13.2 to -8.2)/-5.0 (-6.4 to -3.6) mmHg, -14.3 (-16.8 to -11.9)/-7.6 (-9.1 to -6.2) mmHg, and -20.6 (-23.0 to -18.2)/ -10.4 (-11.8 to -9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was -17.4 (-19.9 to -15.0)/-8.5 (-9.9 to -7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.