A previous pilot study suggested that rizatriptan reduces motion sickness induced by complex vestibular stimulation. In this double-blind, randomized, placebo-controlled study we measured motion sickness in response to a complex vestibular stimulus following pretreatment with either rizatriptan or a placebo. Subjects included 25 migraineurs with or without migraine-related dizziness (23 females) aged 21-45 years (31.0 ± 7.8 years). Motion sickness was induced by off-vertical axis rotation in darkness, which stimulates both the semicircular canals and otolith organs of the vestibular apparatus. Results indicated that of the 15 subjects who experienced vestibular-induced motion sickness when pretreated with placebo, 13 showed a decrease in motion sickness following pretreatment with rizatriptan as compared to pretreatment with placebo (P < 0.02). This significant effect was not seen when subjects were exposed to more provocative vestibular stimulation. We conclude that the serotonin agonist, rizatriptan, reduces vestibular-induced motion sickness by influencing serotonergic vestibular-autonomic projections.