High dose (40 mg) olmesartan medoxomil (OM) blocks the angiotensin II receptor, significantly reducing blood pressure (BP). Adding hydrochlorothiazide (HCTZ) to OM increases efficacy, but has not been evaluated in patients inadequately controlled by OM 40 mg. Patients with grade 2 and grade 3 hypertension with inadequately controlled BP (seated diastolic blood pressure [SeDBP] 90-115 mm Hg and seated systolic blood pressure [SeSBP] 140-180 mm Hg, plus ambulatory BP criteria) after 8 weeks of OM 40 mg open-label treatment were randomized to 8 weeks of double-blind treatment with OM/HCTZ 40/25 (n=140), 40/12.5 (n=278), 20/12.5 mg (n=280) or OM 40 mg (n=274). Treatment with OM/HCTZ 40/25 mg and 40/12.5 mg significantly reduced SeDBP (-5.3 and -3.4 mm Hg, respectively), and SeSBP (-7.4 and -5.2 mm Hg, respectively), vs OM 40 mg monotherapy (P<0.0001 for each) in patients inadequately controlled on OM 40 mg alone. OM/HCTZ 40/12.5 mg reduced SeSBP significantly more than OM/HCTZ 20/12.5 mg (-2.6 mm Hg, P=0.0255), and also produced a further reduction in SeDBP vs the lower dose. All treatments were well tolerated, with similar low proportions of patients reporting treatment-emergent adverse events in all treatment groups. In conclusion, adding HCTZ to OM 40 mg significantly improves BP reductions and target BP rates in harder-to-treat patients and a clear dose-response was observed for efficacy.