Background: A deleterious fetal stress response, although not fully elucidated, may account for poor outcomes after experimental fetal cardiac surgery. We set out to characterize this fetal stress response and its potential role in placental dysfunction. Methods: Fifteen ovine fetuses at gestational day 100 to 114 were placed on extracorporeal support for 30 minutes and were then followed 2 hours after cardiopulmonary bypass. Fetal plasma samples were analyzed for vasopressin, cortisol, and β-endorphin levels, and correlated to fetal hemodynamics and placental gas exchange. Results: Unique temporal patterns of response were seen in release of the three stress hormones. Vasopressin demonstrated the most profound and early response followed by cortisol and β-endorphin, the latter continuing to rise in the post-bypass period. A sharp rise in fetal mean arterial pressure and placental vascular resistance strongly correlated with rising vasopressin levels. Post-bypass deterioration of fetal gas exchange and hemodynamics correlated with the ensuing rise in cortisol and β-endorphin. Rising fetal lactate levels correlated with elevations in all three stress hormones. Conclusions: Fetal cardiopulmonary bypass leads to a profound, early rise in vasopressin concentrations that strongly correlates with placental dysfunction after fetal bypass. Vasopressin may play an important mechanistic role in pathogenesis of this placental dysfunction.