Introduction: Antiphospholipid antibodies (aPL) are the strongest maternal risk factor for preeclampsia, a hypertensive disease of pregnancy. This may be due to the effect of aPL on the turnover of the largest cell in the placenta, the syncytiotrophoblast. Syncytiotrophoblast turnover results in the extrusion of apoptotic trophoblast debris into maternal blood, but in the presence of aPL, the syncytiotrophoblast releases necrotic rather than apoptotic trophoblast debris. To understand how aPL affects the release of necrotic trophoblast debris, we investigated how aPL interacts with the syncytiotrophoblast and how they affect the death-regulating mitochondria. Methods: First trimester placental explants were cultured with fluorescently-labeled human aPL (APS-IgG) or control IgG before being visualized by confocal microscopy. Explants were also cultured with monoclonal aPL ID2 or IIC5 or an isotype-matched control antibody. The location of monoclonal antibodies in the syncytiotrophoblast was determined by immunohistochemistry. The mitochondrial function of aPL-treated explants was assessed using high resolution respirometry and by western blotting cytosolic lysates of aPL-treated placentae. Results: The syncytiotrophoblast internalised APS-IgG and monoclonal aPL ID2 and IIC5 but not respective control antibodies. Respirometry demonstrated that ID2 increased the mitochondrial leak state and depressed the respiratory control ratio. Treatment of explants with both ID2 and APS-IgG increased mitochondrial cytochrome c release, as evidenced by respirometry and western blotting. Conclusion: Once internalised into the syncytiotrophoblast, aPL are in a position to affect mitochondria. Intracellular aPL caused inner mitochondrial membrane leakiness and loss of cytochrome c from the mitochondria to the cytosol, which could have profound effects on the ability of the syncytiotrophoblast to undergo ATP-dependent apoptotic turnover. In the presence of aPL, necrotic death may predominate, leading to the release of necrotic trophoblast debris into maternal blood. Necrotic trophoblast debris may then interact with the maternal endothelium and cause endothelial cell activation, a key step in the development of preeclampsia.