The efficacy, tolerability, and safely of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double- blind, placebo-controlled study. Patients with silting diastalic blood pressure (BP) ≥ 110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with silting diastolic BP > 95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with silting diastalic BP ≥ 90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24 ± 3 hours after treatment) silting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p < 0.001/p < 0.001, respectively. Patients with higher silting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p < 0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP < 90 mm Hg or ≥ 10 mm Hg decrease) and 32% were controlled (diastolic BP < 90 mm Hg). Tolerability and safely profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.