BACKGROUND: Calcitonin gene-related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However, it is unknown to what extent CGRP-induced vasodilation contributes to immediate head pain and whether the migraine-specific abortive drug sumatriptan, a 5-hydroxytryptamine 1B/1D agonist, inhibits CGRP-induced immediate vasodilation and headache. METHODS: We performed a double-blind, randomized, placebo-controlled, crossover study in 18 healthy volunteers. We recorded circumference changes of the middle meningeal artery (MMA) and middle cerebral artery (MCA) using magnetic resonance angiography before and after infusion (20 minutes) of 1.5 µg/min human aCGRP or placebo (isotonic saline) as well as after a 6-mg sumatriptan subcutaneous injection. RESULTS: Compared with placebo, CGRP caused significant dilation of MMA (p = 0.006) and no dilation of MCA (p = 0.69). Sumatriptan caused a marked contraction of MMA (15%-25.2%) and marginal contraction of MCA (3.9% to 5.3%). Explorative analysis revealed that sumatriptan had a more selective action on MMA compared with MCA on the CGRP day (p <0.0001) and on the placebo day (p = 0.007). CONCLUSION: These data suggest that exogenous CGRP dilates extracranial vessels and not intracranial, and that sumatriptan exerts part of its antinociceptive action by constricting MMA and not MCA. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that IV GCRP causes dilation of the MMA but not the MCA in healthy volunteers, and that sumatriptan reverses the dilation of the MMA caused by CGRP.