Cytotrophoblast (CT) cell fusion into a syncytiotrophoblast is obligatory for placentation and mediated by the human endogenous retrovirus (HERV)-W envelope gene Syncytin-1. Abnormal placentation is associated with preeclampsia (PE), HELLP and intrauterine growth restriction (IUGR). In placentogenesis, the MAP-kinase p38alpha regulates PPARgamma/RXRalpha signaling and target genes, like leptin, resistin, ABCG2, and hCG. The aim of this study was to analyze PPARgamma/RXRalpha signaling and target gene regulation using primary CT cultures, the trophoblastic cell line BeWo and placental tissues from patients with normal and abnormal placentation. CT from four different human control placentae and BeWo cells demonstrated that Syncytin-1, other signaling members and CT cell fusions were regulated with PPARgamma/RXRalpha activators troglitazone and 9-cis retinoic acid, via protein kinase A and p38alpha inhibition. Significant discordant regulations between CTs and BeWo were found. Two PPARgamma/RXRalpha-response-elements from upstream regulatory elements and the 5'LTR of HERV-W were confirmed with DNA-protein binding assays using nuclear extracts and recombinant PPARgamma/RXRalpha proteins. These promoter elements were validated with luciferase assays in the presence of PPARgamma/RXRalpha modulators. Furthermore, troglitazone or 9-cis retinoic acid treatment of siRNA-PPARgamma and siRNA-RXRalpha transfected BeWo cells proved the requirement of these proteins for Syncytin-1 regulation. Thirty primary abnormal placentae from PE, HELLP and IUGR patients compared to 10 controls showed significant deregulation of leptin RNA and protein, p38alpha, phospho-p38alpha, PPARgamma, ABCG2, INSL4 and Syncytin-1. Our study characterized PPARgamma/RXRalpha signaling in human CT and cell fusions identifying Syncytin-1 as a new target gene. Based on these results, a disturbed PPARgamma/RXRalpha pathway could contribute to pathological human pregnancies.