The purpose of this study was to assess the effect of soy isoflavone supplementation on quality of life in postmenopausal women. METHODS: A multicenter, randomized, double-blind, placebo-controlled 24-month trial was conducted to assess the effect of 80 or 120 mg of daily aglycone hypocotyl soy isoflavone supplementation on quality of life in 403 postmenopausal women using a validated Menopause-Specific Quality of Life questionnaire. RESULTS: Menopause-Specific Quality of Life domain scores at 1 year and 2 years were similar to baseline. There were no differences in domain scores among treatment groups. CONCLUSIONS: Soy isoflavone supplementation offers no benefit to quality of life in postmenopausal women. © 2012 by The North American Menopause Society.