Background and Objective: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is shown to be superior to renin-angiotensin system inhibitors in terms of blood pressure (BP) lowering effect in several clinical trials. However, there is limited evidence on the BP-lowering effect of sacubitril/valsartan in comparison with amlodipine, a widely used calcium channel blocker (CCB), and potent BP-lowering effect. This study is to investigate the efficacy and safety of sacubitril/valsartan monotherapy compared with amlodipine monotherapy in Japanese patients with essential hypertension. (jRCTs051220165) Methods: This was a multicenter, randomized, open-label, parallel-group, and active-controlled study conducted in Japan. Male or female Japanese patients aged 18 to 79 with either treated or untreated mild to moderate essential hypertension were eligible for this study and randomly assigned to the sacubitril/valsartan 200 mg group or amlodipine 5 mg group. Each study drugs were administered once daily for eight weeks. The primary endpoint was to demonstrate the non-inferiority of sacubitril/valsartan versus amlodipine in mean change from baseline for 24-h systolic blood pressure (SBP) after eight weeks of treatment. Results: A total of 359 patients were randomized in this study (sacubitril/valsartan group n=182, amlodipine group n=177; mean age was 58.3 and 58.1 years, 75.3% and 74.0% were male, baseline BPs were described in Table). At week 8, mean reductions from baseline for mean 24-h SBP in sacubitril/valsartan were non-inferior to that in amlodipine (between-treatment difference: −0.6 mmHg [95% CI: −3.2 to 2.0; P=0.003 for non-inferiority, independent t-test]). In addition, other BP parameters in sacubitril/valsartan were comparable to those in amlodipine (Table). For the investigator-reported adverse events, seven hypotension-related events (3.8%) were observed in sacubitril/valsartan and three events (1.7%) in amlodipine. Conclusions: In Japanese patients with essential hypertension, the BP-lowering effect of sacubitril/valsartan was non-inferior to that of amlodipine, and no marked differences in tolerability were observed. Early initiation of sacubitril/valsartan in hypertensive patients is expected to achieve good BP control, similar to the widely used CCB.