Stroke and stroke-related brain illnesses are the third leading cause of death in the United States (nearly 150,000 in 1990 alone), the largest single cause of neurologic disability, and a major determinant of the late-life dementia that affects many Americans who live into their 70s and beyond. For the 40 million American women over the age of 50, the postmenopausal phase of life is the period of greatest risk of death and disability from cerebrovascular disease. Previous epidemiologic studies suggest that postmenopausal estrogen therapy may reduce the risk of death from cardiovascular and cerebrovascular causes by up to 50%. Uncertainty concerning the validity of these findings has led to calls for a randomized trial of estrogen therapy. In response to these calls, the primary aim of the Women's Estrogen for Stroke Trial (WEST) is to determine whether unopposed estrogen therapy reduces the risk of death or recurrent stroke in postmenopausal women with a recent transient ischemic attack (TIA) or non-disabling stroke. Secondary aims will examine whether estrogen reduces other vascular endpoints (myocardial infarction, TIA, or angina pectoris), or influences physical and/or cognitive functioning. WEST is designed as a randomized, placebo-controlled, double-blind trial of 652 postmenopausal women. Women randomized to active treatment will receive 1 mg of estradiol daily added to best medical care; women randomized to placebo will also receive best available medical care. Enrolled women will be followed for up to 4.5 years with a semi-annual telephone interview and an annual direct interview that will include assessments for neurologic, cardiac, and functional endpoints. To ensure patient safety, women will have an annual gynecologic evaluation with progestogen withdrawal and endometrial biopsy when indicated. In planning the trial, we assumed a rate of death or recurrent stroke in the placebo group of 25% at three years. The calculated sample size of 652 ensures high statistical power (greater than or equal to 80%) to detect a reduction in death or stroke to 15% in the estrogen group. Participation by the Connecticut Neurological Society enabled us to enroll all 20 short-term general hospitals in Connecticut with at least 250 licensed beds in the development of a unique statewide network to recruit patients. The WEST trial is highly significant for the promise it holds for stroke treatment generally, and for the potential health benefits to postmenopausal women specifically.