Background: Several small trials and many observational studies suggest that estrogen treatment in postmenopausal women improves cognition, but 2 large randomized trials have shown harm. The effect of an ultra-low- dose of unopposed transdermal estradiol on cognition and health-related quality of life is unknown. Objective: To investigate the effect of unopposed ultra-low-dose transdermal estradiol on cognitive function and quality of life in postmenopausal women. Design: Randomized, placebo-controlled, double-blind trial with 2-year follow-up. The main outcome of the trial was change in bone density. Changes in cognitive function and quality of life were preplanned secondary outcomes of the trial. Setting: Nine clinical centers in the United States. Participants: Postmenopausal women (N=417), aged 60 to 80 years, with a normal bone density for age and an intact uterus. Intervention: A weekly transdermal patch that delivers estradiol, 0.014 mg/d (n=208), or placebo (n=209). Main Outcome Measures: Seven standardized cognitive tests (a total of 10 scores) administered at baseline and years 1 and 2 to test global cognitive function, verbal and visuospatial memory, language, executive function, and semantic memory. The 36-Item Short-Form General Health Survey was administered to assess health-related quality of life in physical and mental domains. The sample size provided 80% power to detect a standardized effect of 0.29 SD, a small-to-moderate difference. Results: Baseline characteristics were similar in the 2 treatment groups. At 2 years of follow-up, we found no statistically significant differences between treatment groups in change on any of the cognitive test scores or on the 36-Item Short-Form General Health Survey (P>.12 for all). There was no consistent evidence that the effect of treatment on change in cognitive or 36-Item Short-Form General Health Survey scores depended on the level of baseline endogenous estradiol. Conclusion: Postmenopausal treatment with ultra-low-dose unopposed transdermal estradiol for 2 years had no effect on change in cognitive function or in health-related quality of life over 2 years of treatment.