Migraine is a common disabling disease with a complex pathophysiology. Headache is a frequent side effect after intravenous adenosine administration, while adenosine receptor antagonist, caffeine, relieves migraine headache. These observations suggest a possible involvement of adenosine signaling in headache and migraine pathophysiology.In a randomized, double-blinded, placebo-controlled, crossover study, 18 participants diagnosed with migraine without aura received 120 µg/kg/min adenosine or placebo over 20 minutes.Headache intensity, migraine associated symptoms, vital signs, the diameter of the superficial temporal artery (STA), blood flow velocity in the middle cerebral artery (VMCA) and facial skin blood flow were measured at baseline and every 10 minutes until two hours post-infusion start. The primary endpoint was the difference in incidence of migraine attacks after adenosine compared to placebo.Eighteen participants completed the study. We found no difference in incidence of migraine following adenosine (7/18, 39%) compared to placebo (3/18, 17%) (P = 0.29). Fourteen participants (14/18, 78%) reported headache after adenosine compared to placebo (6/18, 33%) (P < 0.01). Adenosine increased heart rate (P < 0.001), facial skin blood flow (P < 0.05) and STA diameter (AUCT0-20min, P = 0.01), and decreased VMCA (AUCT0-20min, P < 0.001) compared to placebo.Adenosine induced headache accompanied by a short-lasting (< 30 min) dilation of intra- and extracerebral arteries. The non-significant migraine induction might be due to the presence of several adenosine receptors with counteracting signaling, highlighting the need of more selective modulators to dissect the implication of adenosine in migraine.