Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.