A single oral dose of 300 μg of clonidine lowered systolic blood pressure by 20 ± 4 mm Hg and diastolic blood pressure by 13 ± 4 mm Hg in five healthy normotensive subjects (controls). Heart rate fell from 56 ± 2 to 52 ± 2 beats/min. In six tetraplegic subjects with physiologically complete chronic cervical spinal cord transection above the level of the sympathetic outflow, the same dose of clonidine did not significantly lower either systolic or diastolic blood pressure. Heart rate fell from 67 ± 4 to 53 ± 2 beats/min. Peak plasma concentrations of clonidine, measured by mass fragmentography, and elimination of the drug from plasma were similar in tetraplegic and control subjects and there was no difference in the incidence of the principal side effects of clonidine-sedation and dry mouth. Although the number of subjects studied is small, the absence of a fall in blood pressure after clonidine in the tetraplegic subjects suggests that the hypotensive action of clonidine in man is dependent on intact descending bulbospinal pathways and is mediated by withdrawal of sympathetic tone and provides dirict evidence that some antihypertensive drugs may lower blood pressure in man by a direct action on the brain.