This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.