Subjects with resistant hypertension present high prevalence of a nondipper blood pressure (BP) pattern, associated with increased risk of cardiovascular events. Nondipping is partly related to the absence of 24-h therapeutic coverage in hypertensives treated with single morning doses. We studied the impact of treatment time on ambulatory BP and clinical characteristics of 1,794 subjects with resistant hypertension, categorized according to the time of treatment (either ingesting all antihypertensive medications upon awakening, or > or =1 drug at bedtime). BP was measured for 48 consecutive hours, and physical activity was simultaneously monitored every minute by wrist actigraphy. The percentage of controlled subjects was higher among those taking medication at bedtime (P < 0.001). Among the 1,306 participants with true resistant hypertension, those ingesting > or =1 drug at bedtime showed significantly lower 24-h mean of systolic BP (SBP)/diastolic BP (DBP) (by 4.1/1.5 mm Hg, respectively; P < 0.015). The difference between groups was more prominent in asleep BP (9.7/4.4 mm Hg, P < 0.001). The awake/asleep BP ratio was significantly higher by 5.8% (P < 0.001) and the prevalence of nondipping lower from 83 to 40% (P < 0.001) in subjects receiving bedtime treatment. This latter group also showed significant lower mean values of glucose, total cholesterol, low-density lipoprotein-cholesterol, fibrinogen, and urinary albumin excretion. In resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each subject. Bedtime treatment was associated with greater clinic and ambulatory BP control, lower prevalence of a high-risk nondipper pattern, and lower values of relevant clinical markers of cardiovascular risk.