This study compared the efficacy and safety of combination angiotensin-receptor blocker (ARB)/calcium-channel blocker (CCB) with hydrochlorothiazide (valsartan/amlodipine/HCTZ 160/5/25mg) vs maximal available combination doses of an ARB with HCTZ (losartan/HCTZ 100/25mg) in the management of stage2 hypertension. After 1 to 2weeks of antihypertensive drug washout, patients with a mean sitting systolic blood pressure (MSSBP) of ≥160 mm Hg and <200mmHg were randomized to valsartan/amlodipine 160/5mg (n=241) or losartan 100mg (n=247). At week3, HCTZ 25mg was added to both treatments. The primary end point, reduction in MSSBP from baseline to week6, was significantly greater in the valsartan/amlodipine group than in the losartan group (least-squares [LS] mean change, -31.8 mm Hg vs -26.4mmHg; P<.001). Additional reductions occurred after titrating to 320/10/25 mg at week6 in the valsartan/amlodipine group and switching from losartan/HCTZ to valsartan/amlodipine/HCTZ (week6, 160/5/25mg; week9, 320/10/25mg) in the losartan group. Achievement of blood pressure <140/90 mmHg also favored the valsartan/amlodipine group. Dizziness was the only adverse event reported in >5% of patients (5.4% valsartan/amlodipine group, 3.6% losartan group). Moderate doses of an ARB/CCB combination with HCTZ reduced blood pressure more effectively than the maximal dose of an ARB with HCTZ.