The active derivatives of vitamin A (the retinoids) play important and multiple roles in mammalian development and homeostasis. We have previously shown that specific retinoic acid receptors are expressed in the chorioallantoic placenta of the mouse and that among these, RXRα is strongly expressed in the developing labyrinthine zone (Sapin, V., Ward, S. J., Bronner, S., Chambon, P., Dollé, P.,Dev. Dyn.208, 199–210, 1997). Here, we show that mouse fetuses with a targeted disruption of the RXRα gene develop defects of the chorioallantoic placenta. Both morphological abnormalities and alterations in the expression of molecular markers were found, mostly confined to the labyrinthine zone of placentas from mid–late gestation mutants. This region exhibited edema, abnormal stasis of maternal blood, and signs of disruption of the endothelial layer of fetal vessels. We also detected a reduction in the number of lipid droplets in the trophoblastic layer and abnormal fibrin deposits in the junctional zone of the mutant placentas. These abnormalities most probably result in an impairment of the functional capacities of exchange between the maternal and fetal circulations in the mutant placentas. Thus, placental defects could represent an extraembryonic cause of lethality for RXRα null mutant fetuses, in addition to the previously described embryonic cardiac defects.