Macrophages represent the second major type of the decidual leukocytes at the fetomaternal interface. Changes in macrophage number and activity are associated with fetal loss and pregnancy complications. Glycodelin-A (GdA) is an abundant glycoprotein in the first trimester decidua. It is involved in fetomaternal defense and early placental development by its regulatory activities on various immune cells. The N-glycosylation of GdA mediates the binding and therefore the activities of the molecule. In this study, we studied the biological activities of GdA on the functions of human monocytes/macrophages. GdA was purified from amniotic fluid by affinity chromatography. GdA treatment did not affect the viability, cell death or phagocytic activity of the monocytes/macrophages. GdA, but not recombinant glycodelin without glycosylation, induced IL-6 production as demonstrated by cytokine array, ELISA and intracellular staining. GdA also induced phosphorylation of extracellular signal-regulated kinases (ERKs) in monocytes/macrophages. The involvement of ERKs in IL-6 induction was confirmed by using pharmacological inhibitors. Co-immunoprecipitation showed that L-selectin on the monocytes/macrophages was the binding protein of GdA. Treatment with anti-L-selectin antibody reduced the GdA binding and GdA-induced IL-6 production. GdA-treated macrophages suppressed IFN-γ expression from cocultured T-helper cells in an IL-6 dependent manner. These results show that GdA interacts with L-selectin to induce IL-6 production from monocytes/macrophages by activating the ERKs signaling pathway. The increased IL-6 production, in turn, suppresses IFN-γ expression from T-helper cells, which may play an important role for inducing a Th-2 polarized cytokine environment that flavors the immuno-tolerance of the fetoplacental unit.