BACKGROUND: Women are prone to neurological complications after cardiac surgery. We have previously reported that treatment perioperatively with the neuroprotectant steroid 17β-estradiol did not improve neurocognitive end-points 4 to 6 wk after surgery for elderly women. In this study, we evaluated the influence of early postoperative neurocognitive dysfunction on quality of life in postmenopausal women undergoing cardiac surgery and whether it is impacted by perioperative 17β-estradiol treatment. METHODS: One hundred seventy-four postmenopausal women randomly received 17β-estradiol or placebo in a double-blind manner beginning the day before surgery and continued until the fifth postoperative day. The patients underwent psychometric testing using a standard battery before surgery and again 4 to 6 wk and 6 mo postoperatively. Quality of life was assessed at baseline and 6 mo after surgery with the SF-36 questionnaire and the Lawton instrumental activities of daily living scale. RESULTS: Complete data were available from 108 women of whom 13% demonstrated postoperative neurocognitive dysfunction. Based on multiple logistic regression analysis, a neurocognitive deficit 4 to 6 wk after surgery was an independent predictor of a lower SF-36 physical component score (P = 0.004) and lower Lawton instrumental activities of daily living scale 6 mo postoperatively (P = 0.026). Treatment with 17β-estradiol (P = 0.003) and smoking status (P = 0.015) were predictors of worse SF-36 mental health component rating. Preoperative lower scores were independently associated with low quality of life postoperatively for all measurements. CONCLUSIONS: Postoperative neurocognitive dysfunction is associated with impaired quality of life in women after cardiac surgery. Perioperative treatment with 17β-estradiol provides no benefits to postoperative quality of life. The relationship between low preoperative and postoperative self-rated health status suggests that some aspects of quality of life in postmenopausal women are not amenable to improvements with cardiac surgery.