Objectives: Subjects with resistant hypertension are at a greater risk for stroke, renal insufficiency, and cardiovascular events than individuals for whom blood pressure (BP) is well controlled by medical therapy. It has been reported that as much as 89% of hypertensive subjects ingest all their antihypertensive medication in the morning. Recent results also indicate that non-dipping is partly related to the absence of homogeneous 24 h therapeutic coverage in subjects treated with single morning doses. We investigated the impact of treatment-time on the BP pattern in subjects with resistant hypertension participating in the Hygia Project, designed to evaluate prospectively cardiovascular risk by ambulatory BP monitoring (ABPM) in primary care centers of Northwest Spain. Methods: We studied 909 subjects with resistant hypertension (547 men), 66.4 ± 11.6 years of age. Among them, 232 subjects were receiving, at the time of evaluation, all their medication on awakening, and 677 were taken at least one antihypertensive drug at bedtime. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h. Results: Among subjects receiving all antihypertensive medication on awakening, the prevalence of extreme-dipper, dipper, non-dipper and riser BP patterns were 2.6, 22.4, 50.0 and 25.0%, respectively. The prevalence of patients with sleep-time relative systolic BP decline <10% (non-dipping, including rising) was significantly lower among subjects receiving medication at bedtime (66.9; P = 0.021), and it was further reduced to 56% when subjects were ingesting all BP-lowering medication at bedtime (P<0.001). The prevalence of a riser pattern was lowest (12%) when subjects were ingesting all drugs at bedtime. No subjects in this later group presented an extreme-dipper pattern. Conclusions: In subjects with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each individual patient. Treatment at bedtime is characterized by increased nighttime BP control and a significantly lower prevalence of a non-dipper and mainly riser BP pattern, associated with increased cardiovascular morbidity and mortality.