The systemic, cardiovascular hemodynamic and biochemical interactions between clonidine and minoxidil were studied in ten patients with refractory and/or accelerated hypertension. Clonidine in oral doses of 150 to 900 micrograms/day decreased mean blood pressure (MAP) 18.6 mm Hg (p less than 0.01), average heart rate (HR) 16.4 bpm (p less than 0.01), limb blood flow 1.63 ml/100 g min (p less than 0.05), plasma renin activity (PRA) 1.13 ng/ml/hr (p less than 0.025), and urinary noradrenaline excretion rate 16.45 micrograms/24hr (p less than 0.05). Clonidine increased the preejection period index (PEPI) 12.4 msec ( p less than 0.001), but did not alter cardiac index (CI), total peripheral resistance index (TPRI), limb vascular resistance nor dopamine beta-hydroxylase activity. When minoxidil in oral doses of 5 to 22.5 mg was added, a further decrease in MAP of 24.2 mm Hg (p less than 0.01) was observed; PEPI decreased 20.6 msec (p less than 0.01), limb blood flow decreased 13.2 mm Hg/min 100 g/ml (p less than 0.05), and total peripheral resistance index decreased 13.3 mm Hg/min m2/L (p less than 0.05). Minoxidil increased average heart rate 8.2 bpm (p less than 0.05), PRA 1.68 ng/ml/hr (p less than 0.05) and urinary noradrenaline excretion rate 5.0 micrograms/24 hr (p less than 0.01). Limb blood flow, cardiac index and dopamine beta hydroxylase activity were not significantly altered by minoxidil. Neither clonidine nor minoxidil affected cardiovascular responses to treadmill exercise. We concluded that clonidine is a useful alternative agent to block a minoxidil-induced increase in sympathetic nervous activity.