The regulation of trophoblast apoptosis is essential for normal placentation, and increased placental trophoblast cell apoptosis is the cause of pathologies such as intrauterine growth retardation (IUGR) and pre-eclampsia. X-linked inhibitor of apoptosis (XIAP) is expressed in trophoblasts, but little is known about the role of XIAP in placental development. In the present study, the function of XIAP in the placenta and in HTR-8/SVneo trophoblasts under hypoxic conditions was examined. In addition, the correlation between XIAP and immortalization-upregulated protein-2 (IMUP-2) was demonstrated in HTR-8/SVneo trophoblasts under hypoxia, based on a previous study showing that increased IMUP-2 induces trophoblast apoptosis and pre-eclampsia. XIAP was downregulated in pre-eclamptic placentas (P < 0.05). In HTR-8/SVneo trophoblasts, XIAP expression was decreased and the expression of apoptosis-related genes was increased in response to hypoxia. Ectopic expression of hypoxia inducible factor (HIF)-1α in HRT-8 SV/neo cells induced the nuclear translocation of XIAP and alterations of XIAP protein stability. Furthermore, hypoxia induced nuclear translocated XIAP co-localized with upregulated IMUP-2 in trophoblast nuclei, and the interaction between XIAP and IMUP-2 induced apoptosis in HRT-8 SV/neo cells. The present results suggest that hypoxia-induced down-regulation of XIAP mediates apoptosis in trophoblasts through interaction with increased IMUP-2, and that this mechanism underlies the pathogenesis of pre-eclampsia. J. Cell. Biochem. 114: 89–98, 2012. © 2012 Wiley Periodicals, Inc.