The adenosine A2A receptor A2AR facilitates effects of calcitonin gene-related peptide and vasoactive intestinal peptide, two important neuropeptides in migraine pathophysiology, and is the molecular target of caffeine, which is used in migraine treatment. We therefore determined whether A2AR gene variation might influence migraine susceptibility. Migraine patients (n = 265) with or without aura and migraine-free controls (n = 154) were assessed and genotyped for six genetic variants spanning the A2AR gene. A six-marker haplotype was more frequent in migraine patients with aura (P < 0.01) but not in patients without aura, compared with the control group. This indicates that A2AR gene variation may contribute to the pathogenesis of migraine with aura.