Background: Proponents of bioidentical estrogens claim that they are superior for treating menopausal symptoms, including depressive symptoms. Small trials examining the effects of bioidentical estrogens on depressive symptoms show conflicting results. We conducted a systematic review to assess the effectiveness and safety of bioidentical estrogens for treatment of depressive symptoms in peri-and postmenopausal women. Methods: We searched the scientific literature for randomized controlled trials of at least 4 weeks duration, comparing bioidentical estrogen with placebo for depressive symptoms in menopausal women. The main outcome measure was improvement in depressive symptoms on a validated scale. Results: We found 12 clinical trials that met inclusion criteria, two of which contained insufficient data for quantitative analysis. In the 10 studies (inclusive of 1208 subjects) for which complete data were available for inclusion in the meta-analysis, bioidentical estrogen had no clinically significant effect on depressive symptoms (standardized mean difference [SMD] -0.02; confidence interval [95% CI] -0.41 to + 0.38). Pooled studies were highly heterogeneous, and numerous approaches to reducing heterogeneity were unsuccessful. Subgroup analyses showed no significant difference in effect for women treated with adjunctive progestogen, women treated with unopposed estrogen, perimenopausal, or postmenopausal and mixed populations. A possible benefit in perimenopausal women treated with unopposed estradiol may have been diluted by studies including older postmenopausal women whose depressive symptoms were unrelated to menopause. Conclusions: In this first systematic review of bioidentical hormone replacement therapy, we found that bioidentical estrogen has no clear benefit in treating depressive symptoms in menopausal women, but heterogeneity of available studies limits the potential for definitive conclusions. Future research should compare bioidentical estrogen with nonbioidentical estrogen for treatment of depressive symptoms in perimenopausal women.