Background: During two decades of migraine provocation studies with naturally occurring signalling molecules, vasodilators such as prostaglandin E2, prostaglandin I2 (prostacyclin) and prostaglandin D2 were shown to be able to induce headache in man. To elucidate the role of inflammation and vasodilatation in the generation of headache, we investigated whether the pro-inflammatory and vasoconstricting prostanoid prostaglandin F2α (PGF2α) would cause headache in a human model of headache.Methods: Twelve healthy volunteers were randomly allocated to receive 3.5 μg/kg/min PGF2α or placebo over 20 min in a two-way crossover study. We recorded headache intensity on a verbal rating scale, middle cerebral artery blood flow velocity (VMCA) and the diameters of the superficial temporal artery (STA) and radial artery (RA).Results: We found no difference in the area under the curve (AUC) for immediate headache (0-90 min) between PGF2α and placebo (p = 0.144). The McNemar's test showed no difference in the incidence of immediate and delayed headache between verum and placebo (p = 0.500 and p = 1.000, respectively). There was no difference in VMCA (p = 0.776) and in the diameter of the STA (p = 0.460) or RA (p = 0.780) between PGF2α and placebo.Conclusion: The present study shows that PGF2α, unlike vasodilating prostaglandins, does not provoke headache. We suggest that the vasodilating abilities of prostaglandins are important for the induction of experimental headache in healthy volunteers.