Introduction: An 8-week trial of amlodipine/valsartan/hydrochlorothiazide (Aml/Val/HCTZ) for moderate or severe hypertension demonstrated more-pronounced blood pressure (BP)-lowering effects compared with dual-component therapies. To elucidate the effects of time and baseline BP on the observed responses, exploratory analyses were performed. Methods: Patients aged 18-85 years with mean sitting systolic BP (MSSBP) 145 to <200 mmHg and mean sitting diastolic BP (MSDBP) 100 to <120 mmHg were randomized to Aml 10 mg/Val 320 mg/HCTZ 25 mg; Val 320 mg/HCTZ 25 mg; Aml 10 mg/Val 320 mg; or Aml 10 mg/HCTZ 25 mg. During the first 2 weeks, regimens 0077-7 11 were force-titrated in two stages. Results: All least-square mean reductions in MSSBP and MSDBP (baseline to Week 3 and end of study) were significantly greater with triple therapy than with each dual therapy in the overall population and the severe systolic subgroup (baseline MSSBP ≥180 mmHg; except vs. Aml 10 mg/Val 320 mg at Week 3). At Week 3, more patients on triple therapy achieved MSSBP reductions of ≥60, ≥50, ≥40, ≥30, and ≥20 mmHg (2.5%, 9.7%, 23.2%, 46.9% and 74.5%, respectively) than those on dual therapy (1.1%-2%, 5.6%-5.9%, 14.5%-16.7%, 33.5%-39.1%, and 58.8%-65.5%, respectively); this was also true at study endpoint. End-of-study MSSBP reductions were greater in triple-therapy recipients who had higher (vs. lower) baseline MSSBPs. LSM reductions ranged from 27.2 mmHg for baseline MSSBP 145 to <150 mmHg, to 49.6 mmHg for baseline MSSBP ≥180 mmHg. All treatments were well tolerated regardless of baseline MSSBP. Conclusion: Aml 10 mg/Val 320 mg/HCTZ 25 mg triple therapy is highly effective in reducing BP compared with dual components early in therapy, and systolic BP-lowering effects were proportionate to hypertension severity. © Springer Healthcare 2009.