Preeclampsia and fetal growth restriction are conditions associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes elevated apoptosis. Recently, trophoblast stem (TS) cells had been successfully derived. FGF-4 locates in the inner cell mass (ICM) of blastocyst and TS cells have fibroblast growth factor receptor-2 (FGFR-2). To identify whether FGF-4 protects hypoxia-induced apoptosis in TS cells, this study was carried out. TS cells were cultured up to 48 h in standard (PO2 = 20%) or hypoxic (PO2 = 3%) conditions. TS cells were very vulnerable against exposure to hypoxia for 48 h but embryonic stem (ES) cells were very resistant to hypoxiamediated apoptosis. Death of TS cells bears the typical hallmarks of apoptosis as determined by DNA laddering. FGF- 4 and epidermal growth factor (EGF) protected the hypoxia-mediated cell death of trophoblast but granulocyte-macrophage colony stimulating factor (GMSF) and transforming growth factor-beta (TGF-beta) did not protect. In conclusion, we speculate that the effects of FGF-4 on apoptosis in trophoblasts may play an important role in protecting the placenta from hypoxic injury in pregnancy related with placental hypoperfusion.