The syncytiotrophoblast is formed at the placental periphery through cytotrophoblast fusion, which depends on Human Endogenous Retrovirus-encoded Envelope proteins Syncytin-1 and Syncytin-2. In the current study, the role of Major Facilitator Superfamily Domain Containing 2A (MFSD2a), the Syncytin-2 receptor, in trophoblast fusion and its expression in normal vs. pre-eclampsia placentas were studied. Forskolin-induced fusion of BeWo cells first parallelled an increase in MFSD2a expression. The MFSD2a signal localized in the cytoplasm and at the plasma membrane. Knockdown of MFSD2a expression confirmed its importance in BeWo fusion. Furthermore, reduced MFSD2a expression was noted in severe pre-eclamptic placentas. These data thus support the importance of MFSD2a in trophoblast fusion and placenta development.