Regional cerebral blood flow (rCBF) and cerebral vasomotor responses to 5% CO2 inhalation were measured before and after pharmacologic μ- or β-adrenoceptor manipulation in Migraine (M) and Cluster headaches (C). Responses of 77 vascular headache patients (M =66 and C = 11) were compared to those of 15 Muscle contraction headache (MCH) and 64 normal volunteers. Oral drugs were: Peripheral μ-adrenoceptor stimulator:isometheptene (Midrin(r)), peripheral μ-blocker:dihydroergotoxin (Hydergine(r)), centrally acting μ-blocker:clonidine (Catapres(r)), peripheral β-blocker:propranolol (Inderal(r)), peripheral β-stimulator:isoproterenol (Isuprel(r)). Peripheral μ stimulation markedly reduced rCBF during headache but effect lessened after headache subsided in M and C. Peripheral μ-blockade and β-stimulation increased CBF in M and C. Peripheral β-blockade markedly decreased CBF during headache in M but caused only small CBF reductions when headache-free. Peripheral adrenoceptor effects on rCBF in M and C were greatest on most recent headache side. Central effects of clonidine were opposite (greatest on non-headache side). Excessive CO2 responses were greatest on side of headache. After peripheral μ-stimulation, peripheral μ-blockade, peripheral β-stimulation or blockade, CO2 responses were restored toward normal but not after central μ-blockade. In MCH. contrary to M and C, μ-stimulation had no effect on CBF or CO2 responses. There appears to be an asymmetrical adrenoceptor disorder in M and C possibly due to sympathetic denervation-hypersensitivity.