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Introduction: Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension., Methods: Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5-10/1.25-2.5/5-10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months., Results: Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point., Conclusion: FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.