The terminal event in the establishment of the haemochorial placenta in the human is the invasion of trophoblasts into the maternal vessels, a process in which trophoblasts interact directly with the vascular endothelium and degrade the vascular basement membrane and the tunica elastica of the vessels. To further understand this heterotypic cellular interaction, we investigated the expression by human trophoblasts of the vascular cell adhesion molecule platelet-endothelial cell adhesion molecule-1 (PECAM-1) as a possible mediator of the adhesive interaction between trophoblasts and endothelium. In vitro, human trophoblasts were found to express PECAM-1 mRNA and protein. Indirect immunofluorescence indicated a diffuse staining pattern, which was most intense in a subpopulation of trophoblast cells. Co-incubation of trophoblasts with endothelial cells showed interaction between these two cell types with strong expression of PECAM-1 at points of trophoblast-endothelial cell contact, suggesting that this cell adhesion molecule participates in this heterotypic cell interaction. Immunohistochemical localization of PECAM-1 in chorionic villi and first trimester implantation sites showed that, in vivo, only extravillous interstitial and endovascular trophoblasts were positive. In first trimester placentae, villous trophoblast and extravillous trophoblast in other locations than around or within the decidual vessels did not express this molecule. In term placentae, villous trophoblast did not express these adhesion molecules except for two specimens examined. This study demonstrates that PECAM-1 is expressed by a subset of human trophoblasts in vitro and in vivo. Its tissue localization suggests that PECAM-1 is important in mediating the adhesive interaction between trophoblasts and maternal vascular endothelium during the process of haemochorial placentation. Regulation of PECAM-1 expression by human trophoblasts may play a critical role in normal and abnormal vascular invasion during implantation and placentation.