Previous reports have described down-regulation of E-cadherin in trophoblasts differentiating to an invasive phenotype. This study shows the localization of E-cadherin in a prospective design with stereological sampling of fetal and maternal first, second and third trimester tissue. E-cadherin was observed in villous cytotrophoblasts, and in non-proliferating, intermediate trophoblasts (IT) within cell columns and islands in intrauterine, ectopic and partial molar placentas. Highly proliferating IT with cytological atypia in complete molar placentas were also E-cadherin-positive. E-cadherin was present in trophoblasts throughout the anchoring cell columns. Trophoblasts undergoing epithelial mesenchymal transformation (EMT) detaching from the distal cell columns and deeper located single extravillous interstitial trophoblasts (EVT) showed E-cadherin-negative breaches in the cell membrane. Prior to the late second trimester, the relative number of E-cadherin-positive single EMT and EVT differed from the total number of cytokeratin-positive trophoblasts. Intraluminal, endovascular and perivascular trophoblasts adjacent to the maternal vessels were also E-cadherin-positive, but a highly varying pattern was observed at different ages of gestation. Our results indicate a temporary shift in E-cadherin expression in extravillous trophoblasts possessing a migrating and invasive potential. Functional E-cadherin may be restored as trophoblasts aggregate in the decidua and the vessel wall after completion of migration.