Doxazosin (DOX), an α-adrenergic antagonist with demonstrated antihypertensive effects, is frequently chosen for combination therapy in uncontrolled patients who are already receiving other antihypertensive drugs. We investigated the dose and administration-time dependent effects of the new DOX gastrointestinal therapeutic system (GITS) formulation on the 24-hour pattern of blood pressure (BP) in patients with refractory hypertension. We studied 29 patients with uncontrolled essential hypertension (16 men and 13 women), 62.3±8.9 (mean±SD) years of age, who were receiving an average of 3.1 antihypertensive drugs, including 4 mg/day of DOX GITS. The patients were randomly assigned to receive an additional dose of 4 mg/day of DOX GITS either at the same time as the original dose (and thus receiving 8 mg/day at a fixed time of the day), or at a different circadian time (and thus receiving 4 mg of DOX both after awakening as well as before bedtime). BP was measured by ambulatory monitoring at 20-min intervals during the day (07:00 to 23:00 hours) and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of therapy. Circadian parameters were obtained for each group of patients before and after intervention by population multiple-components analysis. There was a very small reduction of BP after doubling the dose of DOX GITS at the same time of the day (1.0 and 1.6 mm Hg in the 24-hour mean of systolic and diastolic BP, respectively; P>0.629). The BP reduction was much larger and highly statistically significant (8.4 and 6.1 mm Hg in the 24-hour mean of systolic and diastolic BP, respectively; P=0.004) when the same 8 mg/day of DOX were distributed in two doses of 4 mg taken approximately every 12 hours. This BP reduction was similar for the diurnal and the nocturnal means of BP. In patients with refractory hypertension taken a combination therapy including DOX GITS, there is little benefit in terms of BP control by doubling the dose of DOX at the same time of day. Results indicate a significant added benefit and a proper 24-hour coverage when 4 mg of DOX GITS are used both at awakening as well as before bedtime. These dose and administration-time dependent effects should be taken into consideration when increasing the dose of DOX GITS in uncontrolled hypertensive patients.