Trisomy 21 is the most frequent genetic anomaly leading to mental retardation, and is prenatally diagnosed by fetal karyotyping usually performed on amniotic fluid cells. Amniocentesis is offered to patients according to three criteria: maternal age (over 38 years), fetal anomalies detected by ultrasonography, and abnormal maternal serum markers most of which are produced by the placenta. Placental development in trisomy 21 is poorly understood. We therefore studied the syncytiotrophoblast, which plays a key role in pregnancy through its involvement in fetal-maternal exchanges and in the secretion of pregnancy-specific hormones. The multinucleated syncytiotrophoblast is formed by the differentiation and fusion of mononucleated cytotrophoblasts. We show that in trisomy 21, syncytiotrophoblast formation is defective and/or delayed. This anomaly is associated with defective synthesis and the secretion of pregnancy-specific hormones. These findings enhance the understanding of placental serum markers used in the prenatal screening of trisomy 21 and clarify the impact of placental abnormalities on fetal development in trisomy 21.