Since phytoestrogens (e.g. biochanin A, coumestrol, daidzein, genistein and glycitein) are structurally similar to estrogen, they mimic estrogen function. Phytoestrogens consist in certain edible plants, especially in soybeans. Among them, interestingly, equol that has the greatest estrogenic activity is generated from daidzein by gut microbes. Therefore, the relationship between phytoestrogens and gut (including intestinal cells and bacteria) is being watched with strong interest. In this paper, we revealed that all-trans retinoic acid (RA) dramatically enhances cytotoxicity of several phytoestrogens against U937 cells. While β-estradiol and phytoestrogens tested showed no effect on the viability of U937 cells in the absence of RA, 10 μM coumestrol, (±)-equol and genistein brought about remarkably reduced viability of U937 cells at 24 h (to ~15%, ~7% and ~35%, respectively) in the presence of 1 μM RA. In particular, the cytotoxicity of (±)-equol was drastically enhanced in the presence of RA. Moreover, very interestingly, (±)-equol showed no effect on the viability of human peripheral neutrophils even in the presence of RA. As is well known, human monoblastic leukemia U937 cells have been used as an in vitro model for macrophage that exists in intestine and plays significant roles to maintain intestinal homeostasis. These data suggest that equol not only can serve as an effective modifier in therapy for leukemia in combination with RA but also may affect the maintenance of intestinal homeostasis.