Estrogen and related hormone therapies activate estrogen receptors, which in turn regulate genes for several cardiovascular disease (CVD) risk factors. Relatively little is known, however, about the impact of genetic variation in estrogen receptor alpha (ESR1) on CVD risk.To investigate whether the ESR1 c.454-397T>C polymorphism is associated with CVD risk.Prospective study of 1739 unrelated men and women from the population-based offspring cohort of the Framingham Heart Study, who were followed up from 1971 to 1998.Total atherosclerotic CVD events, defined as recognized or unrecognized myocardial infarction (MI), angina pectoris, coronary insufficiency, intermittent claudication, coronary heart disease death, or atherothrombotic stroke (n = 178); major atherosclerotic CVD, defined as recognized acute MI, coronary insufficiency, coronary heart disease death, or atherothrombotic stroke (n = 83); and recognized acute MI (n = 59).Twenty percent of participants (n = 352) were homozygous for the ESR1 c.454-397C allele. After adjustment for covariates (age, sex, body mass index, hypertension, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, and cigarette smoking), the CC genotype was significantly associated with major atherosclerotic CVD, with an odds ratio of 2.0 (95% confidence interval [CI], 1.3-3.2; P =.004) compared with individuals with the CT or TT genotypes. Participants with the CC genotype had 3.0-fold greater odds of MI (95% CI, 1.7-5.2; PC is causally related to MI risk or in linkage disequilibrium with 1 or more causal variants remains to be determined. These findings support the importance of estrogen receptors in CVD susceptibility, especially in men. Estrogen receptor variation also has potential to explain recent conflicting data regarding the effects of hormone therapy on CVD susceptibility in women.