This study investigated an aggressive treatment program for stage 2 systolic hypertension (pretreatment systolic blood pressure [SBP] ≥160 mm Hg) using the angiotensin receptor blocker olmesartan medoxomil (OM) and hydrochlorothiazide (HCTZ). In this open-label, 16-week trial, 170 subjects received OM 20 mg/d for 3 weeks. If seated SBP/diastolic BP remained ≥120/80 mm Hg, subjects were advanced to successive 3-week courses of OM 40 mg/d, OM/HCTZ 40/12.5 mg/d, and OM/HCTZ 40/25 mg/d. OM 20 mg/d reduced mean SBP by 16.9 mm Hg (P<.001), and there were further dose-dependent decreases in mean SBP to a maximum of 34.5 mm Hg with OM/HCTZ 40/25 mg/d. At study end, 75.1% of subjects achieved SBP goal (<140 mm Hg) and 16.0% achieved SBP normalization (<120 mm Hg). Treatment was well tolerated at all doses. The addition of HCTZ did not change serum potassium levels but resulted in a dose-independent but not symptomatic increase in serum glucose and uric acid. The authors conclude that an OM-based regimen, with or without HCTZ in conventional doses, is effective in controlling and normalizing BP in stage 2 systolic hypertension.