Immunohistochemical localization of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, the first and rate-limiting enzyme in tryptophan metabolism along the kynurenine pathway, has been studied in order to better understand the physiological significance of these enzymes at the maternal-fetal interface of human pregnancy with a gestational age of 7 weeks (n = 1) and term placentas (37-40 weeks of gestation, n = 5). Indoleamine 2,3-dioxygenase-1 protein immunoreactivity was found in glandular epithelium of the decidua and the endothelium of the fetal blood vessels in the villous stroma with some additional positive cells in the villous core and in the decidua. The syncytiotrophoblast stained strongly for indoleamine 2,3-dioxygenase-2. Immunoreactivity of kynurenine, the immediate downstream product of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism, showed the same localization as that of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, suggesting these are functional enzymes. Interferon-γ added to placental villous explant culture markedly stimulated expression level of both mRNA and immunoreactivity of indoleamine 2,3-dioxygenase-1. The different cellular expression and interferon-γ sensitivity of these enzymes at the maternal-fetal interface suggests distinct physiological roles for each enzyme in normal human viviparity.