Prostacyclin [prostaglandin I2(PGI2)] activates and sensitizes meningeal sensory afferents. In healthy subjects PGI2 triggers headache in healthy subjects. However, the migraine-eliciting effect of PGI2 has not been systematically studied in patients with migraine. We hypothesized that intravenous infusion of the stable prostacyclin analogue epoprostenol would trigger migraine-like attacks in migraineurs. We infused 10ngkg-1 min-1 PGI2 or placebo over 25 min in 12 migraineurs without aura in a controlled, double-blind, cross-over study and recorded headache intensity and associated symptons, velocity in the middle cerebral artery (VMCA) and diameter in the superficial temporal artery. In the period 0-14 h, 12 subjects reported headache on PGI2 day compared with three subjects on placebo day (P = 0.004), and six subjects fulfilled the criteria for an experimentally induced migraine-like attack compared with two subjects on placebo (P = 0.219). During infusion and post-infusion phases the AUC under the headache curve on PGI2 was significantly larger than on placebo (P<0.05). There was a significant V MCA decrease (P = 0.015) and superficial temporal artery diameter increase (P < 0.001) on PGI2 compared with placebo. In conclusion, PGI2 may trigger a migraine-like attack in migraine sufferers. We suggest sensitization of perivascular nociceptors and arterial dilation as the mode of action of PGI2-induced headache and migraine-like attacks.