A single oral dose of clonidine hydrochloride (300 μg) lowered systolic blood pressure by 20±2 mmHg and diastolic blood pressure by 15±2 mmHg in seven healthy normotensive subjects. Resting supine plasma noradrenaline concentration fell from 2.42±0.47 nmol/l before dosing a minimum of 0.59±0.18 nmol/l at 6 hr. The value subsequently rose and was not significantly different from that before the dose at 12 hr. There was a significant reduction in urinary free catecholamine excretion in the first 12 hr after dosing. Resting supine plasma renin activity before dosing was 0.95±0.16 pmol of angiotensin I h-1 ml-1 of plasma and rose significantly after clonidine to 3.50±0.39 pmol of angiotensin I h-1 ml-1 of plasma at 6 h. By 12 h plasma renin activity had returned to control values. When the same subjects were studied on a control, drug-free, day under the same conditions, there was no significant change in blood pressure or plasma noradrenaline. Although plasma renin activity rose during this control day, it was significantly lower than after clonidine. In normotensive subjects single doses of clonidine lower blood pressure and are associated with a reduction of sympathetic nervous activity. Delayed elevation of plasma renin activity may be secondary to the fall in blood pressure. There is no evidence for an overshoot of sympathetic activity after a single dose of clonidine.