The unique MHC phenotype of the human and nonhuman primate placenta has suggested a potential role in maternal-fetal immune tolerance, pregnancy success, and maternal as well as fetal well-being. In the rhesus monkey (Macaca mulatta) a nonclassical MHC class I molecule, Mamu-AG, is a putative homologue of HLA-G and is hypothesized to play a role in maternal-fetal immune interactions during pregnancy. Rhesus monkeys were passively immunized during the second week after implantation with a mAb against Mamu-AG. Passive immunization altered the growth and vascularization of the fetal placenta, the placental modification of maternal endometrial vessels, the maternal leukocyte response to implantation, and the differentiation of epithelial and stromal cells in the endometrium. These data are the first to demonstrate in vivo the importance of MHC class I molecules expressed on primate trophoblasts in establishing an important environment for pregnancy success through coordinated interactions between endometrial and fetal tissues.