Neurocognitive dysfunction is an important source of patient morbidity and mortality after cardiac surgery that may disproportionately affect postmenopausal women. 17beta-Estradiol limits the extent of ischemic neuronal injury in a variety of experimental models. The purpose of this study was to evaluate whether perioperative administration of 17beta-estradiol to postmenopausal women reduces the frequency of neurocognitive dysfunction after cardiac surgery. One hundred seventy-four postmenopausal women not on estrogen replacement therapy who were undergoing primary coronary artery bypass graft surgery and/or valve surgery with cardiopulmonary bypass were prospectively randomized to receive in a double-blinded manner either 17beta-estradiol or placebo beginning the day before surgery and continuing for 5 days postoperatively. The patients were evaluated before and after surgery with the National Institutes of Health Stroke Scale and a psychometric test battery. There were no differences in the frequency of neurocognitive dysfunction (primary outcome) between patients randomized to perioperative 17beta-estradiol (n=86) and those randomized to placebo (n=88) 4 to 6 weeks after surgery (17beta-estradiol, 22.4% versus placebo, 21.4%, P=0.45). The mean scores on tests of psychomotor speed were worse in women in the 17beta-estradiol group than in the placebo group at the 4- to 6-week (P=0.005) postoperative testing sessions. Perioperative treatment with 17beta-estradiol did not result in improved neurocognitive outcomes in postmenopausal women undergoing cardiac surgery.