Recent studies from our laboratory have indicated that the transcription factor activator protein-2α plays a critical role in the differentiation of human villous cytotrophoblast cells to syncytiotrophoblast cells. However, little is known about the expression of activator protein-2α in placentas from pathologic pregnancies. This study compares the expression of activator protein-2α in placentas from high-risk pregnancies to gestational age-matched controls. Paracentral sections from grossly unremarkable areas of 10 placentas from each group of pregnancies complicated by mild preeclampsia, severe preeclampsia, diabetes mellitus, chronic hypertension, and fetal growth restriction and 10 control cases of placentas from normal pregnancies matched for gestational age were double immunostained for activator protein-2α and E-cadherin. The total numbers of cytotrophoblast cells and syncytiotrophoblast nuclei and the numbers of activator protein-2α-positive and activator protein-2α-negative nuclei in both of these cell types were counted by 2 pathologists blinded to disease status, in 10 representative×40 high-power fields for each placenta. Abnormal placental maturation in most of pathologic pregnancies was evidenced by a 1.5- to 1.7-fold lower expression ratio of syncytiotrophoblast cell to cytotrophoblast cell. Activator protein-2α in syncytiotrophoblast cells was lower in mild preeclampsia, diabetes mellitus, hypertension, and fetal growth restriction (P<.0001 in each instance) and was higher by 2-fold in severe preeclampsia, although this increase was not statistically significant (P=.3). Because activator protein-2α has been shown to be critical for villous cytotrophoblast cell differentiation, our findings suggest that abnormalities in the activator protein-2α cascade of transcription factors and/or signaling molecules may contribute to the pathogenesis of the abnormal maturation in placentas in certain types of high-risk pregnancies. The different pattern of activator protein-2α expression in mild and severe preeclampsia clearly suggests that these conditions may have 2 independent pathogenic mechanisms.