Background: The Women's Health Initiative (WHI) clinical trial of conjugated equine estrogens (CEEs), involving 10 739 postmenopausal women with hysterectomy, aged 50 to 79 years, was stopped early owing to lack of overall health benefit and increased risk of stroke. Because CEE is still prescribed for treatment of menopausal symptoms and prevention of osteoporosis, it is important to understand the overall impact of this therapy on health-related quality of life (HRQOL). Methods: All participants completed 6 specific measures of quality of life at baseline and 1 year, and a subsample (n=1189) also completed the questions 3 years after randomization. Changes in scores were analyzed for treatment effect. Results: Randomization to CEE was associated with a statistically significant but small reduction in sleep disturbance at year 1 compared with baseline (mean benefit, 0.4 points on a 20-point scale) and a statistically significant but small negative effect on social functioning (mean effect, -1.3 points on a 100-point scale). There were no significant improvements due to CEE in the areas of general health, physical functioning, pain, vitality, role functioning, mental health, depressive symptoms, cognitive function, or sexual satisfaction at year 1. A subgroup examined 3 years after baseline had no significant benefits for any HRQOL outcomes. Among women aged 50 to 54 years with moderate to severe vasomotor symptoms at baseline, CEE did not improve any of the HRQOL variables at year 1. Conclusion: In this trial of postmenopausal women with prior hysterectomy, oral CEE did not have a clinically meaningful effect on HRQOL.