Clonidine was administered into the left vertebral artery of anesthetized cats. A dose-response curve of the lowering effect on intraocular pressure (IOP) has been made and compared with the dose-response cure obtained after intravenous administration. A more pronounced decrease in IOP after the first route of administration became evident. The effect is not secondary to a stronger reduction of blood pressure by centrally injected clonidine. Distribution experiments with 14C-clonidine revealed no direct connection between the vertebral arteries and the blood supply of the eye. For 2 h the concentrations in the eye are somewhat lower than after intravenous administration. Therefore, the IOP-lowering effect is not due to a direct influence of clonidine on the eye. It is submitted that the clonidine-induced reduction in IOP is at least in part due to a central mechanism, in which the stimulation of central alpha-adrenoceptors and adrenergic neurons may be involved. The relevance of this hypothesis with regard to a possible central regulation of IOP is discussed.