This randomized, double-blind, placebo-controlled multicenter study was designed to evaluate the efficacy, tolerability, and safety of candesartan cilexetil in a diverse population of patients with severe systemic hypertension (diastolic blood pressure > or =110 mm Hg). After a placebo run-in period, patients were given hydrochlorothiazide (HCTZ) 12.5 mg once daily for 1 week. A total of 217 patients with sitting diastolic blood pressure >95 mm Hg while receiving HCTZ were then randomized in a 2:1 ratio to receive candesartan cilexetil or placebo once daily for 4 weeks. Candesartan cilexetil was started at 8 mg and titrated to 16 mg if needed for blood pressure control; background HCTZ was continued in both groups. Candesartan cilexetil was significantly more effective than placebo in lowering trough diastolic and systolic blood pressure. The mean change in trough sitting diastolic blood pressure from the end of the HCTZ run-in period to the week 4 endpoint (primary study endpoint) was -9.1 mm Hg with candesartan cilexetil and -3.1 mm Hg with placebo (p = 0.0001). A higher percentage of patients treated with candesartan cilexetil than placebo responded to treatment (53% vs 29%) and achieved diastolic blood pressure <90 mm Hg (32% vs 15%). Subgroup analyses indicated that candesartan cilexetil was especially effective in patients with higher trough diastolic blood pressure at randomization, and it was significantly more effective than placebo in both black and nonblack patients alike as well as in women and men. Candesartan cilexetil was safe and well tolerated, with an adverse-event profile comparable to placebo. These results demonstrate that candesartan cilexetil added to background HCTZ therapy is effective and well tolerated in lowering blood pressure in patients with severe systemic hypertension.