The expression of the non-classical MHC class I molecule HLA-G is normally restricted to the placenta during pregnancy, where it is found on fetal endothelial cells and on invasive cytotrophoblast cells, specifically those at the maternal / fetal interface. Its precise physiological role has yet to be defined. HLA-G may have nonimmune functions relating to angiogenesis and placentation, but most evidence suggests that it protects fetal cells from lysis by maternal uterine NK cells, which are found in large numbers around invading trophoblast cells. This effect is due to specific interaction with inhibitory receptors expressed on NK cells. We have examined the hypothesis that another function of HLA-G is to inhibit NK cell migration. Using an in vitro transmigration assay system, we present data to support this hypothesis. NK cell migration across porcine endothelial cells transfected with HLA-G1 was specifically inhibited compared to migration across HLA-A2-transfected monolayers. HLA- G1 had no influence on the migration of a control T lymphocyte line. These results support the idea that in vivo, HLA-G may inhibit NK cell traffic across the placenta.