BACKGROUND: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochlorothiazide 300/25 mg. RESULTS: Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and 6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison. CONCLUSIONS: Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for managing hypertension. TRIAL REGISTRATION: EudraCT (No. 2006-005799-42).