Objective-: To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thromboembolism. Methods and results-: The design was a nested case-control study in the Women's Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: 359 cases of coronary heart disease, 248 of stroke, and 217 of venous thromboembolism. Six estrogen receptor-α polymorphisms and 1 estrogen receptor-β polymorphism were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and 1 year after randomization. The polymorphisms were not associated with risk of vascular events and did not modify the increased risks of coronary heart disease, stroke, or venous thromboembolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin to hormone therapy was noted for estrogen receptor-1 IVS1 (intron number 1)-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and estrogen receptor-1 IVS1-1415 (interaction P<0.0001, corrected P=0.014). Conclusion-: Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on plasmin-antiplasmin, a marker of coagulation and fibrinolysis. However, screening for estrogen receptor polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful in making decisions about hormone therapy treatment. © 2011 American Heart Association, Inc.