Peri-implantation mouse embryos and extraembryonic membranes were examined immunohistochemically for the expression of the cell-cell adhesion molecule (cell-CAM) 120/80. Cell-CAM 120/80 was seen along the lateral borders of all cells in the blastocyst but became undetectable on trophoblastic giant cells, some mononuclear trophoblastic cells and parietal yolk sac cells when blastocysts were cultured in vitro. In postimplantation embryos in vivo, all parts of the early egg-cylinder reacted with the antibody to cell-CAM 120/80 except for the cells of the parietal endoderm and the primary trophoblastic giant cells. In the late stage egg-cylinder, no cell-CAM 120/80 was seen on the cells of the primitive mesoderm or on the primordial germ cells. The germ cells in genital ridges and fetal gonads remained cell-CAM 120/80-negative throughout the fetal stages of development. In the extraembryonic membranes, the visceral yolk sac, amnion, and the cells of the placental labyrinth were cell-CAM 120/80-positive, whereas, the parietal yolk sac cells and the spongiotrophoblast cells were negative. These data show that cell-CAM 120/80 is found on cells arranged into epithelial layers in the early embryo and extraembryonic tissues, but is not expressed in the dissociated cells differentiating from these epithelia. Thus, the expression of cell-CAM 120/80 appears to be developmentally regulated.