PPAR-gamma/RXR heterodimers play a key regulatory role in murine placental development. We report here that PPAR-gamma and RXR-alpha are highly expressed in cultured primary extravillous cytotrophoblasts (EVCT) isolated from human first-trimester placenta. Using this cell culture model, we showed that PPAR-gamma agonists inhibit EVCT invasion, whereas PPAR-gamma or pan-RXR antagonists promoted EVCT invasion by themselves and abolished PPAR-gamma agonist-mediated effect. Together these data underscore an important function of PPAR/RXR heterodimers in the modulation of trophoblast invasion.