To help resolve the uncertain relationship between migraine headache and ischemic stoke, we performed a hospital-based, case-control study. Eighty-nine cases ages 15-65 with a head computed tomography (CT) scan supported diagnosis of ischemic stroke were matched to 178 control subjects. Using information obtained by telephone interview, the patients were placed into three categories according to explicit criteria: classic migraine; common migraine; and no migraine headache. Overall, the association between migraine and ischemic stroke is significantly increased only in patients with classic migraine [odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-6.6]. In addition, classic migraine does not appear to increase ischemic stroke when hypertension, diabetes or smoking are present; however, when these other risk factors are absent, classic migraine is strongly and significantly associated with the risk of ischemic stroke [no hypertension, OR = 5.7 (95% CI 1.6-20.2); no diabetes, OR = 3.4 (95% CI 1.2-9.3); non-smoker OR = 4.3 (95% CI 1.2-15.0)]. Since none of the migraine patients in our study had a migrainous stroke, an underlying disorder other than prolonged vasospasm may be responsible for the observed increased risk. Our data suggest that classic migraine may be a marker for patients at increased risk for ischemic stroke unrelated to a migraine attack.