BACKGROUND: Migraine with aura is thought likely to be caused by cortical spreading depression (CSD). Tonabersat inhibits CSD, and we therefore investigated whether tonabersat has a preventive effect in migraine with aura. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, 40 mg tonabersat once daily was compared with matched placebo in patients who had at least one aura attack per month during the past 3 months. Randomisation was by computer-generated list. Patients kept a detailed diary to enable objective diagnosis of each attack as migraine with aura, migraine without aura, or other type of headache. Primary endpoints were a reduction in aura attacks with or without headache and a reduction in migraine headache days with or without an aura. Analysis was per protocol. This trial is registered, number NCT00332007. FINDINGS: 39 patients were included in the study, of whom 31 were included in the statistical analysis of efficacy. Median (IQR) attacks of aura were reduced from 3.2 (1.0-5.0) per 12 weeks on placebo to 1.0 (0-3.0) on tonabersat (p=0.01), whereas the other primary outcome measure, median migraine headache days with or without aura, was not significantly different between placebo and tonabersat groups (3.0 days in each group; p=0.09). Tonabersat was well tolerated but overall had more side-effects than placebo. INTERPRETATION: Tonabersat showed a preventive effect on attacks of migraine aura but no efficacy on non-aura attacks, in keeping with its known inhibitory effect on CSD. The results support the theory that auras are caused by CSD and that this phenomenon is not involved in attacks without aura. FUNDING: Minster Pharmaceuticals; Lundbeck Foundation.