Epimedium brevicornum maxim, a nonleguminous medicinal plant, has been found to be rich in phytoestrogen flavonoids. Results from a 24-month randomized double-blind placebo-controlled clinical trial showed that Epimedium-derived phytoestrogen flavonoids were able to exert beneficial effects on preventing bone loss in late postmenopausal women, without resulting in a detectable hyperplasia effect on the endometrium. Introduction: We performed a 24-mo randomized double-blind placebo-controlled clinical trial for evaluating the effect of the Epimedium-derived phytoestrogen flavonoids (EPFs) on BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness in postmenopausal women. Materials and Methods: One hundred healthy late postmenopausal women, with a natural menopausal history within 10 ∼18 yr and with a BMD T-score at the lumbar spine between −2 and −2.5 SD, were randomized into EPF treatment group (n = 50; a daily dose of 60 mg Icariin, 15 mg Daidzein, and 3 mg Genistein) or placebo control group (n = 50). All participants received 300 mg element calcium daily. BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness were measured at baseline and 12 and 24 mo after intervention. Results: Eighty-five participants completed the trial. The patterns of BMD changes were significantly different between the EPF treatment group and placebo control group by repeated-measures ANOVA (p = 0.045 for interaction between time and group at femoral neck; p = 0.006 for interaction between time and group at lumbar spine). BMD was found with a decreased tendency in the placebo control group at 12 (femoral neck: −1.4%, p = 0.104; lumbar spine: −1.7%, p = 0.019) and 24 mo (femoral neck: −1.8%, p = 0.048; lumbar spine: −2.4%, p = 0.002), whereas EPF treatment maintained BMD at 12 (femoral neck: 1.1%, p = 0.285; lumbar spine:1.0%, p = 0.158) and 24 mo (femoral neck: 1.6%, p = 0.148; lumbar spine: 1.3%, p = 0.091). The difference in lumbar spine between the two groups was significant at b...