We tested the hypothesis that epidermal growth factor (EGF) limits hypoxia-induced apoptosis in cultured human trophoblasts by phosphorylation of the pro-apoptotic protein BAD. Cytotrophoblasts were isolated from placentas of uncomplicated pregnancies at 38–40 weeks gestation. Primary trophoblasts or transfected JEG3 trophoblast cells were cultured in <1% or 20% oxygen in the presence or absence of EGF and signaling pathway inhibitors. BAD, GFP-BAD, 14–3-3, Bcl-X_L and neoepitopes formed during apoptotic cleavage of cytokeratin 18 intermediate filaments were quantified using immunoblotting. Cultures immunostained by fluorescent antibodies were analyzed by confocal microscopy for BAD and GFP. FRET was used to detect molecular interaction between endogenous BAD and GFP-BAD. We found EGF increased the phosphorylation of BADser112 under standard culture conditions. Whereas hypoxia enhanced apoptosis and increased phosphorylation of both BADser136 and BADser155, hypoxia diminished phosphorylation of BADser112, and this effect was reversible by EGF. Transfected GFP-BAD, which directly interacted with endogenous BAD by colocalization and FRET, enhanced hypoxia-induced apoptosis in JEG3 cells. EGF reduced apoptosis in hypoxic JEG3 cells that overexpressed GFP-BAD but not in cells overexpressing GFP-BAD that harbored a serine to alanine mutation at the 112 site. Co-immunoprecipitation studies showed that EGF reduced the pro-apoptotic interaction of BAD with Bcl-X_L. The effect of EGF on phosphorylation of BADser112 was dependent upon the action of p38 MAPK. We conclude that EGF signals via p38 MAPK to increase phosphorylation of BADser112, and thereby limit trophoblast apoptosis.