CGRP may play a causative role in migraine. A double-blind crossover study in 12 migraine patients without aura showed that intravenous infusion of human α-CGRP (2 μg/min) for 20 minutes caused headache and migraine, while placebo did not. The median peak headache score was 1.0 in the CGRP group vs. 0 in the placebo group (P<0.01). During the following 11 hours, all patients experienced headaches after CGRP vs. one after placebo (P=0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P=0.006). In three patients after CGRP, but in none after placebo, the delayed headache met IHS criteria for migraine without aura. These results suggest that increased CGRP during migraine attacks may play a causative role. CGRP is a neurotransmitter involved in neurogenic inflammation and cerebral vasodilation. The study supports the idea that CGRP may directly cause migraine rather than being a secondary effect. The findings have implications for the treatment of migraine, as CGRP antagonists may be effective. The study also highlights the importance of understanding the pathophysiology of migraine and the potential of CGRP as a therapeutic target.CGRP may play a causative role in migraine. A double-blind crossover study in 12 migraine patients without aura showed that intravenous infusion of human α-CGRP (2 μg/min) for 20 minutes caused headache and migraine, while placebo did not. The median peak headache score was 1.0 in the CGRP group vs. 0 in the placebo group (P<0.01). During the following 11 hours, all patients experienced headaches after CGRP vs. one after placebo (P=0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P=0.006). In three patients after CGRP, but in none after placebo, the delayed headache met IHS criteria for migraine without aura. These results suggest that increased CGRP during migraine attacks may play a causative role. CGRP is a neurotransmitter involved in neurogenic inflammation and cerebral vasodilation. The study supports the idea that CGRP may directly cause migraine rather than being a secondary effect. The findings have implications for the treatment of migraine, as CGRP antagonists may be effective. The study also highlights the importance of understanding the pathophysiology of migraine and the potential of CGRP as a therapeutic target.