Single nucleotide polymorphism (SNP) genotype frequencies were examined to determine whether variation in 6 estrogen-related genes was associated with differences in self-reported depressive symptoms in women. In this substudy of the Study of Women's Health Across the Nation (SWAN), DNA from a multiracial/multiethnic sample of 1,538 African American, Caucasian, Chinese, and Japanese women aged 42 to 52 years participating in SWAN was genotyped. Depressive symptoms were measured with the Center for Epidemiologic Studies-Depression (CES-D) scale. After excluding data from women taking antidepressants (n=103), statistical models were fit using multivariate logistic regression to predict the association of estrogen-related polymorphisms with the dichotomized CES-D score. Among Caucasian women, those with the CYP1A1 rs2606345 CC and AC genotypes had approximately 2-fold greater odds of having depressive symptoms than did those with the AA genotype (95% confidence intervals [CIs], 1.33 to 4.66 and 1.25 to 3.14, respectively). African American women with the CC genotype of the same SNP had 10-fold greater odds of having more depressive symptoms than did women with the AA genotype (95% CI, 1.20 to 86.20). In Japanese women, the odds of depressive symptoms were nearly 5-fold higher among those with CYP 19 rs936306 TT genotype (95% CI, 1.10 to 22.17) than in women with the CC genotype and 9.6-fold higher (95% CI, 2.01 to 45.81) than in women with the CT genotype. The odds of depressive symptoms among Chinese women with the 17HSD rs615942 TT genotype were nearly 11-fold higher than in those with the GT genotype (95% CI, 1.94 to 60.84) and >7-fold higher than in those with the GG genotype (95% CI, 1.13 to 51.82). These data provide evidence that selected genes involved in estrogen synthesis and metabolism increase the odds of more depressive symptoms in women who are premenopausal or perimenopausal.