Equol is an isoflavone (IF) metabolite produced by intestinal microbiota in a subset of people consuming dietary soy. Equol producers may show different responses to soy foods and phenotypes related to cancer risk. Here, we assessed the effects of soy IF, endogenous microbial equol production, and dietary racemic equol in a 3 × 2 × 2 factorial experiment using gnotobiotic apoE-null mice (n = 9-11/group/sex). At age 3-6 wk, equol-producing microbiota were introduced to one-half of the colony (n = 122). At age 6 wk, mice were randomized to receive a diet that contained 1 of 3 protein sources: casein and lactalbumin, alcohol-washed soy protein (low IF), and intact soy protein (high IF), with total IF amounts of 0, 42, and 566 mg/kg diet, respectively. One-half of each diet group also received racemic equol (291 mg/kg diet). After 16 wk of dietary treatment, serum isoflavonoid profiles varied with sex, soy IF amount, and intestinal microbiota status. There were no treatment effects on tissues of male mice. In females, reproductive tissue phenotypes differed by equol-producing ability (i.e., microbiota status) but not dietary equol or IF content. Equol producers had lower uterine weight, vaginal epithelial thickness, total uterine area, endometrial area, and endometrial luminal epithelial height compared with nonproducers (P < 0.05 for all), with an association between microbiota status and estrous cycle (P > chi-square = 0.03). Exogenous equol reduced expression of progesterone receptor (PGR) and the proliferation marker Ki67 (P < 0.0001) in vaginal epithelium and endometrium; for endogenous equol, only PGR was reduced (P < 0.0005). Our findings indicate that equol diminishes estrogen-dependent tissue responses in apoE-null mice.