BACKGROUND European hypertension guidelines estimate that up to 15-20% of hypertensive patients are not controlled on a dual antihypertensive combination and require three or more different antihypertensive drug classes to achieve blood pressure (BP) control. OBJECTIVE This study in patients with moderate-to-severe hypertension assessed the efficacy and safety of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg to a range of olmesartan medoxomil (OLM)/amlodipine (AML) doses. METHODS This phase III, multicentre study had a randomized, double-blind, parallel-group design that included a double-blind safety run-in and a double-blind treatment period. METHODS Enrolled patients were screened and previous therapy was discontinued if required. During a 2-week, double-blind, safety run-in period (Weeks 0-2), patients were randomized to receive placebo, OLM/AML 20 mg/5 mg, OLM/AML 40 mg/5 mg or OLM/AML 40 mg/10 mg. During an 8-week, double-blind treatment period (Weeks 3-10), patients were allocated to eight groups depending on their initial treatment. They were either randomized to continue with the same dose of OLM/AML, or have HCTZ 12.5 mg or 25 mg added to treatment. METHODS The primary endpoint was formulated before data collection began. It was the change in mean diastolic BP (DBP) from baseline to Week 10 in groups with HCTZ added to OLM/AML, compared with the corresponding dual OLM/AML therapy. RESULTS Of 3195 patients who were screened, 2690 were randomized. Patients in every triple OLM/AML/HCTZ group had significantly greater mean reductions in DBP (p ≤ 0.032 for each comparison) and systolic BP (SBP) by Week 10 (p ≤ 0.0034 for each comparison), compared with patients on the corresponding OLM/AML therapy dose. The significant improvements in DBP and SBP reduction with triple OLM/AML/HCTZ therapy, compared with dual OLM/AML therapy, were observed after 4 and 6 weeks of therapy. Patients in each triple therapy group also had a significantly higher rate of BP <140/90 mmHg threshold achievement (p ≤ 0.05 for each treatment comparison), compared with the dual OLM/AML groups. In three of the OLM/AML/HCTZ groups (40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg and 40 mg/10 mg/25 mg), BP <140/90 mmHg threshold achievement by Week 10 was over 70%. Across the triple and dual combination therapy groups, treatment was well tolerated and no safety concerns for either treatment were identified. CONCLUSIONS Adding HCTZ to a range of OLM/AML dose combinations is well tolerated and improved BP control by significantly lowering DBP and SBP and significantly increasing BP threshold achievement in patients with moderate-to-severe hypertension. BACKGROUND Registered at ClinicalTrials.gov identifier as NCT00923091.