This study was undertaken to compare the antihypertensive efficacy of zofenopril 30 mg + hydrochlorothiazide 12.5 mg fixed combination versus zofenopril alone in patients with essential hypertension with and without the metabolic syndrome, according to National Cholesterol Education Program-Adult Treatment Panel III criteria. After a 4-wk placebo washout period, 463 patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95–115 mm Hg) aged 1 8 to 75 y were randomly assigned 2:1:1 to treatment with zofenopril + hydrochlorothiazide, zofenopril, or hydrochlorothiazide for 12 wk in an international, multicenter, double-blind, parallel-group study. DBP and systolic blood pressure changes with treatment were calculated. The first 12 wk of treatment were followed by a 24-wk open-label period during which only safety was assessed. Reported here is a subanalysis of the main study results, performed in patients with and without metabolic syndrome, limited to a zofenopril+hydrochlorothiazide versus zofenopril comparison. The antihypertensive effect of zofenopril+hydrochlorothiazide or zofenopril was similar in patients with (77%) and without metabolic syndrome. In patients with and without metabolic syndrome, however, DBP and systolic blood pressure reductions were significantly greater with zofenopril+hydrochlorothiazide (with metabolic syndrome: 14±8/21±14 mm Hg; without metabolic syndrome: 15±7/23±14 mm Hg) than with zofenopril alone (with metabolic syndrome: 10±9/11 ±15; without metabolic syndrome: 12±10/14±18 mm Hg). The safety of the 2 treatments was similar in patients with and without metabolic syndrome. The fixed combination of zofenopril+hydrochlorothiazide improved the efficacy of zofenopril alone. This effect was particularly evident in patients with metabolic syndrome, in whom blood pressure control is more difficult to achieve and who are at greater risk for cardiovascular events.