Mammalian pregnancy is an intriguing immunological phenomenon where the semiallogeneic fetus is not rejected. Tolerance toward the fetus involves a number of mechanisms associated with modifications of the immune status of the mother. In this study, we strongly suggest a novel mechanism for fetal evasion of maternal immune attack, based on the engagement and down-regulation of the activating NK cell receptor NKG2D on PBMC by soluble MHC class I chain-related proteins A and B (collectively termed MIC). A similar immune escape pathway was previously described in tumors. We found that MIC mRNA was constitutively expressed by human placenta and could be up-regulated upon heat shock treatment. Our immunomorphologic studies showed that the MIC expression in placenta was restricted to the syncytiotrophoblast. Immunoelectron microscopy revealed a dual MIC expression in the syncytiotrophoblast: on the apical and basal cell membrane and in cytoplasmic vacuoles as MIC-loaded microvesicles/exosomes. Soluble MIC molecules were present at elevated levels in maternal blood throughout normal pregnancy and were released by placental explants in vitro. Simultaneously, the cell surface NKG2D expression on maternal PBMC was down-regulated compared with nonpregnant controls. The soluble MIC molecules in pregnancy serum were able to interact with NKG2D and down-regulate the receptor on PBMC from healthy donors, with the consequent inhibition of the NKG2D-dependent cytotoxic response. These findings suggest a new physiological mechanism of silencing the maternal immune system that promotes fetal allograft immune escape and supports the view of the placenta as an immunoregulatory organ.