Migraine therapy using low doses of clonidine has been based on the proposal that clonidine directly inhibits vascular smooth muscle reactivity. In anaesthetized monkeys in which internal and external carotid vascular resistances were measured, the only significant effects of clonidine administered acutely (0.5 and 2 microgram x kg-1 i.v.) or chronically (2 microgram x kg-1 i.m. daily for 7 days) on cranial vascular responses to the constrictors noradrenaline and 5-hydroxytryptamine, and the dilators histamine, prostaglandin E1 and bradykinin, were small potentiations of some of the responses. Acute clonidine initially increased blood pressure and constricted the cranial vasculature, then induced hypotension without involvement of the cranial circulation. It also decreased the external carotid vasoconstrictor response to low frequency cervical sympathetic nerve stimulation. The low chronic dose of clonidine had no hypotensive effect. The pressor response to common carotid occlusion was inhibited by both acute and chronic clonidine. These experiments thus provide no evidence that clonidine inhibits cranial vascular reactivity at doses equivalent to those used in migraine.