Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B () in maternal and placental cells. Although the role of in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% ) or normoxic (8% ) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% in comparison to C 8% . Therefore, other pathways may be responsible for activation. One such pathway depends on the activation of by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of Ser536 in the nucleus, but only in cells incubated with PE serum at 2% . Thus, the p53/RSK1 complex might play a critical role in the activation of in trophoblastic cells and preeclamptic placentas