Bosentan, a specific mixed antagonist of endothelin receptors with no vasoconstrictor activity, inhibits neurogenic plasma extravasation (NPE) within rat dura mater. This would predict efficacy in aborting migraine attacks, without causing cardiovascular side-effects. We investigated the efficacy of 250 mg i.v. bosentan in a randomized, double-blind, placebo-controlled, clinical trial. Improvement from moderate/severe to mild/no headache at 2 h (primary efficacy measure) occurred in 5/23 (22%) of bosentan-treated and in 9/25 (36%) of placebo-treated patients (effect difference -14%; 95% CI -52%, 24%). Thus, inhibition of NPE may not predict clinical efficacy of experimental antimigraine drugs. Vasoconstrictor action may be needed.