However, during normal pregnancy, extravillous trophoblast cells invade maternal uterine tissues. The interstitial trophoblast penetrates decidual tissues reaching the inner third of the myometrium. A subset of the interstitial trophoblast, transforms uterine spiral arteries into large-bore conduits to enable the adequate supply of nutrients and oxygen to the placenta and thus to the fetus. Controlled invasion by trophoblast of uterine decidua, myometrium and spiral arteries, is essential for normal fetoplacental development. The balance between trophoblast apoptosis and proliferation represents a mechanism to control normal trophoblast invasion. In this regard leptin, was described as an important cytokine regulating trophoblast survival, promoting growth and preventing the apoptotic process. These effects may be of physiological relevance since trophoblastic cells are an important source of increased leptin production during pregnancy. Moreover, leptin levels are increased under stressful condition for placenta cells such as preeclampsia or gestational diabetes. This overproduction of leptin may be helpful to prevent the stress-mediated apoptosis of the trophoblastic cells. However, little is known about the molecular mechanisms underlying these effects. Leptin activation of MAPK pathway has been previously found to be the mechanism whereby leptin promotes cell survival preventing apoptosis. In trophoblastic JEG-3 cells we have found that leptin prevents the apoptotic process triggered by the deprivation of serum by means of the activation of MAPK pathway, but little is known about the mechanisms involved. In this study, we employed BeWo human choriocarcinoma cells and Swan-71 cells. Human placental explants from healthy donors were also studied to confirm the physiological relevance of the mechanisms involved in leptin survival effect. BeWo cells maintain many characteristics of human trophoblast cells and have been widely used to study placental function. Swan-71 cell line has attributes that are characteristic of primary first trimester trophoblast cells. The Swan-71 cells are positive for the expression of cytokeratin 7, vimentin and HLA-G and exhibit a cytokine and growth factor profile that is similar to primary trophoblast cells. Swan-71 cells also express the long isoform of leptin receptor. They represent a valuable model for in vitro trophoblast studies. In this study we confirmed that leptin diminishes apoptosis in placental cells by virtue of the decrease of the Caspase-3 activation both in BeWo cells and in human placental explants. Moreover, when endogenous leptin expression was inhibited using an oligonucleotide complementary to leptin mRNA, cleaved Caspase-3 peptide increased. Leptin also diminished the cleavage of PARP, a nuclear DNA-binding protein that influences DNA repair, DNA replication, modulation of chromatin structure and apoptosis. These results reinforced the notion of leptin as a survival factor.