Background -Estrogen receptor α(ESR1) gene variation is associated with a range of important estrogen-dependent characteristics, including responses of lipid profile and atherosclerotic severity to hormone replacement therapy, coronary heart disease risk, and migraine. The roles that reproductive steroids play in cerebrovascular pathophysiology and ischemia are an important area of investigation. Given that there is a significantly higher risk of myocardial infarction among men with the CC genotype (PP of PvuII) of c.454-397T >C (rs2234693), we asked whether this genotype is associated with a higher risk of stroke. Methods -Relative risk of stroke by genotype was determined in 2709 participants of the Second Northwick Park Heart Study, white males with a mean baseline age 56 years and follow up 10.5 years. Results -Compared with participants with the ESR1 c.454-397CT or TT genotype, those with the CC genotype had a relative risk of stroke of 1.92 (95%confidence interval, 1.06 to 3.48, P=0.03) after adjustment for age, primary care practice; additional adjustment for body mass index, serum cholesterol and triglyceride levels, hypertension, diabetes, and smoking status. Exclusion of stroke cases with coronary heart disease gave results that were essentially unchanged. Conclusions -In this study, subjects with the common ESR1 c.454-397CC genotype have a substantial increase in risk of stroke. In another publication, other ESR1 variation was associated with migraine. We thus hypothesize that estrogen receptor variation may provide a basis for the established re lationship among estrogens, migraine, and stroke. Background-Estrogen receptor alpha (ESR1) gene variation is associated with a range of important estrogen-dependent characteristics, including responses of lipid profile and atherosclerotic severity to hormone replacement therapy, coronary heart disease risk, and migraine. The roles that reproductive steroids play in cerebrovascular pathophysiology and ischemia are an important area of ​​investigation. Given a significant higher risk of myocardial infarction among men with the CC genotype (PP of PvuII) of c.454-397T> C (rs2234693), we asked whether this genotype Methods-Associated risk of stroke by genotype was determined in 2709 participants of the Second Northwick Park Heart Study, white males with a mean baseline age 56 years and follow up 10.5 years. Results -Compared with participants with the ESR1 c.454-397CT or TT genotype, those with the CC genotype had a relative risk of stroke of 1.92 (95% confidence interval, 1.06 to 3.48, P = 0.03) after adjustment for age, primary care practice; additional adjustment for body mass index, serum cholesterol and triglyceride levels, hypertension, diabetes, and smoking status. Exclusion of stroke cases with coronary heart disease gave results that were essentially unchanged. Conclusions -In this study, subjects with the common ESR1 c.454-397CC genotype have a substantial increase in risk of stroke. In another publication, other ESR1 variation was associated with migraine. There therefore hypothesize that estrogen receptor variation may provide a basis for the established re lationship among estrogens, migraine, and stroke.