In younger postmenopausal women, estrogen is thought to be protective against coronary heart disease. The mechanism for this effect is likely to be an inhibition of the development of atherosclerosis. However, in older postmenopausal women with established atherosclerosis, the initiation of estrogen therapy may cause coronary artery plaque instability and rupture, resulting in coronary thrombosis and myocardial infarction. Compared with these findings of coronary disease prevention in younger women, estrogen therapy has been linked to an increased risk of ischemic stroke in both younger and older postmenopausal women, although the risk is small and the event rate in younger women is considered to be rare. Here, we provide an argument that the mechanism for stroke risk in younger women is not based on atherosclerotic disease, as occurs in older women for both coronary disease and stroke, but is related to thrombosis. Susceptibility for stroke is increased in women, and various factors leading to thrombosis may explain this risk. This notion is supported by data that estrogen regimens that decrease the risk of venous thrombosis (lower oral doses and transdermal therapy) may not be associated with an increase in ischemic stroke risk.