The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial that studied low-dose aspirin (325 mg every other day) therapy among 22,071 US male physicians aged 40 to 84 years. Annual follow-up questionnaires requested information on the occurrence of numerous medical conditions including migraine. At the end of 60 months, morbidity follow-up was 99.7% complete, and the reported consumption of aspirin or other platelet-active drugs was 86% in the aspirin group and 14% in the placebo group. Of those randomized to aspirin, 661 (6.0%) reported migraine at some time after randomization, as compared with 818 (7.4%) of those allocated to the placebo group, representing a statistically significant 20% reduction in recurrence rate. The rate of self-report of ordinary headache was similar in the two groups. These data indicate that migraine is mediated, at least in part, by the effects of platelets and suggest that low-dose aspirin should be considered for prophylaxis among those with a history of established migraine.