Potentiation of venospastic action of 5-HT by methysergide and ergotamine was demonstrated in man by using venomotor receptors as substrate in a venoconstriction test. 5-HT facilitation was observed only when anti-migraineous drugs were tested in concentrations similar to those expected after therapeutic administration. When ergotamine and methysergide were used in higher concentrations, the expected antagonism to 5-HT was clearly demonstrated. It is concluded that methysergide and ergotamine therapy is not antiserotonergic. These drugs act as partial agonists of 5-HT. Methysergide and ergotamine facilitation of 5-HT activity may occur at peripheral vasomotor receptors, or centrally in the brain. This latter probably is consistent with the postulated central nature of pain in essential headache.