Abstract Background Blood pressure is reported to be insufficiently controlled in >50% of patients with hypertension. Guidelines for the management of hypertension recommend using drugs with different mechanisms of action when >1 agent is needed to achieve the blood pressure target. The combination of an angiotensin II receptor blocker and a calcium channel blocker is recommended as the preferred antihypertensive medication combination, and candesartan cilexetil (CC) and amlodipine besilate (AML) are commonly used in Japan. Objective The objective of our study was to determine if the combination of CC 8 mg and AML 5 mg has a greater blood pressure-lowering effect than monotherapy with either component, and if the combination of CC 4 mg and AML 2.5 mg has a greater blood pressure-lowering effect than placebo. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in Japanese patients with mild-to-moderate essential hypertension. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive the combination of CC 4 or 8 mg with AML 2.5 or 5 mg, CC 8 mg monotherapy, AML 5 mg monotherapy, or placebo once daily in the fasting or fed state for 12 weeks. The primary end point was change from baseline in trough diastolic blood pressure, and the secondary end point was change from baseline in trough systolic blood pressure at the end of treatment. Tolerability was assessed based on adverse events, vital signs, and physical findings. Results Of 548 patients who received placebo during the run-in period, 444 were randomized to receive CC 8 mg/AML 5 mg (CC/AML 8/5 mg) (n = 101), 8/2.5 mg (n = 36), 4/5 mg (n = 36), 4/2.5 mg (n = 35), CC 8 mg (n = 100), AML 5 mg (n = 100), or placebo (n = 36). These 444 patients included 272 men and 172 women. The mean (SD) age was 56.9 (10.7) years and the mean baseline BP was 153.4/95.7 mm Hg. The antihypertensive effect in the CC/AML 8/5 mg group (−27.4/−16.3 mm Hg) was significantly higher than in the CC 8 mg group (−13.9/−7.8 mm Hg) or the AML 5 mg group (−19.9/−11.2 mm Hg) in terms of reduction in the seated trough diastolic blood pressure and systolic blood pressure (both P < 0.0001). The incidence and severity of adverse events in the CC/AML combination groups did not differ significantly from those in the monotherapy and placebo groups. Conclusions In Japanese adult patients with mild-to-moderate essential hypertension, CC/AML 8/5 mg combination therapy was more effective in lowering blood pressure than CC 8 mg or AML 5 mg monotherapy. These combinations were also well tolerated. Japan Pharmaceutical Information Center registration number: Japic CTI-101054.