This post hoc analysis of the Irbesartan/Hydrochlorothiazide (HCTZ) Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial evaluated the efficacy and safety of fixed-dose irbesartan/HCTZ in patients with isolated systolic hypertension. Adults with uncontrolled systolic blood pressure (SBP) (140-179 mm Hg; 130-179 mm Hg in type 2 diabetes) after 4 weeks or more of antihypertensive monotherapy once-daily treatment with placebo for 4-5 weeks, followed by HCTZ 12.5 mg for 2 weeks, irbesartan/HCTZ 150/12.5 mg for 8 weeks, and then irbesartan/HCTZ 300/25 mg for 8 weeks, in a prospective, multicenter, open-label, single-arm study. In patients with isolated systolic hypertension (n = 443) and the total study population (n = 736), irbesartan/HCTZ treatment for 16 weeks provided comparable mean blood pressure (BP) reductions from baseline (21.4/10.1 mm Hg vs 21.5/10.4 mm Hg; p < .001 vs baseline) and high SBP control rates (74% vs 77%). Patients with isolated systolic hypertension and concomitant type 2 diabetes experienced smaller BP reductions (17.9/8.7 mm Hg vs 22.9/10.7 mm Hg) and lower rates of SBP control (< 130 mm Hg, 47%) than those without diabetes (< 140 mm Hg, 87%). BP reductions from baseline and SBP control rates were similar across isolated systolic hypertension subgroups (> or = 65 vs < 65 years, sex, race, and metabolic syndrome status). Irbesartan/HCTZ was well tolerated, with drug-related adverse events (dizziness, < or = 3%; upper respiratory tract infection, < or = 2%) occurring with similar rates in the isolated systolic hypertension and total population. Fixed-dose irbesartan/HCTZ combination treatment provided effective and well-tolerated BP lowering in a diverse population of patients with isolated systolic hypertension.