The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I2, (PGI2)) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI2 might induce headache and vasodilatation of cranial vessels. A stable analog of PGI2 epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (Vmean MCA) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI2 day and no subjects reported headache on the placebo day (p = 0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p = 0.005). PGI2 caused headache associated with the dilatation of STA (AUC, p < 0.001), but no significant dilatation of the MCA (AUC, p = 0.508). These data indicate that PGI2 induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.