Reducing systolic blood pressure (BP) is of major benefit to patients with isolated systolic hypertension, but lowering normal diastolic BP may be harmful in terms of cardiovascular risk. Effects of different drugs on systolic BP, diastolic BP, and pulse pressure are therefore of interest. The NatriliX SR versus CandEsartan and amLodipine in the reduction of systoLic blood prEssure in hyperteNsive patienTs study (X-CELLENT) was a randomized, double-blind, placebo-controlled study comparing the effects of three drugs on these BP components. Patients with systolic–diastolic or isolated systolic hypertension (n = 1758) received indapamide (1.5 mg) sustained release (SR), candesartan (8 mg), amlodipine (5 mg), or placebo once daily for 12 weeks. Compared to placebo all active treatments reduced all BP components significantly (P < .001). For the patients with isolated systolic hypertension (n = 388), the three treatments significantly reduced systolic BP, but only indapamide SR did not change diastolic BP and thus reduced pulse pressure significantly relative to placebo (P = .005). In an ancillary study using ambulatory BP monitoring (n = 576), all three treatments significantly reduced BP components during 24 h relative to placebo. Changes in systolic BP and pulse pressure were similar with the three treatments, but the reduction in diastolic BP was significantly smaller, and therefore more favorable, with indapamide SR compared with candesartan (P = .039). In patients with isolated systolic hypertension (n = 106), indapamide SR reduced 24-h systolic BP significantly more than amlodipine (P = .037), and only indapamide SR reduced 24-h pulse pressure significantly relative to placebo (P = .03). All three drugs were well tolerated. This distinctive BP-lowering profile of indapamide SR seems highly beneficial when compared to the either of candesartan or amlodipine.