Recent data indicated that local production of Fas ligand (FasL) by cells of the eye and testis may confer immune tolerance at these sites. In the present study, we examined the in vivo and in vitro patterns of expression of FasL in the human placenta to provide a potential mechanism through which the fetus is afforded protection against the cytolytic actions of lymphocytes present within maternal decidua across gestation. Immunohistochemical staining of first trimester human placental tissue sections revealed the presence of FasL in cytotrophoblasts in free floating villi, anchoring villi, and cytotrophoblastic islands. FasL staining was also pronounced in syncytiotrophoblasts of term placenta indicating that FasL expression is maintained across gestation. Multiple molecular forms of FasL, suggestive of altered patterns of glycosylation, were detected in extracts of term placenta, amnion and chorion by Western blotting. In addition, in vitro expression of FasL was demonstrated to increase 2 to 3-fold during differentiation of primary cultures of cytotrophoblasts isolated from human term placentas. Local production of FasL by human cytotrophoblasts provides a mechanism through which cytotrophoblasts may induce immune tolerance and self-regulate survival during invasion and subsequent placentation.