Placental development is markedly abnormal in women bearing a fetus with trisomy 21, with defective syncytiotrophoblast (ST) formation and function. The ST arises from cytotrophoblast (CT) fusion and plays an essential role by secreting hCG, which is essential to placental development. In T21 pregnancies, CT do not fuse and differentiate properly into ST leading to the secretion of an abnormal and weakly bioactive hCG. In this study, we report for the first time, a marked decrease in the number of mature hCG receptor (LH/CG-R) molecules expressed at the surface of T21-affected CT. The LH/CG-R seems to be functional based on sequencing that revealed no mutations or deletions and binding of recombinant hCG as well as endogenous hCG. We hypothesize that weakly bioactive hCG and lower LH/CG-R expression may be involved in the defect of ST formation. Interestingly, the defective ST formation is mimicked in normal CT cultures by using LH/CG-R siRNA which result in a lower hCG secretion. Furthermore, treatment of T21-affected CT with recombinant hCG overcomes in vitro the T21 phenotype, allowing CT to fuse and form a large ST. These results illustrate for the first time in trisomy 21 pathology, how abnormal endogenous hCG signaling impairs human placental development.