CRIPTO-(CR)1 is a protein associated with tumorigenesis and metastasis. Here we demonstrate that CR-1 expression in normal and creta placentas is associated with various degrees of uterine invasion. Cytokeratin (CK) and CR-1 protein expression was visualized by immunohistochemical staining of formalin-fixed, paraffin-embedded placental specimens (control placentas, n = 9; accreta, n = 6; increta, n = 10; percreta, n = 15). The pattern of extravillous trophoblast (EVT) cell morphology was distinctive in creta placentas: densely-compacted cell columns and large star-shaped cells with a typically migratory phenotype, not common among third trimester control placentas. Quantification revealed higher CR-1 immunoreactivities in accreta (P = 0.001), increta (P = 0.0002), and percreta placentas (P = 0.001) than in controls. In contrast to controls, there was a significant positive relationship between CR-1 and CK reactivity in all creta placentas (accreta, P = 0.02; increta, P = 0.0001, and percreta, P = 0.025). This study demonstrated CR-1 expression in the placental bed, its increased expression in creta placentas, and EVT cells as the main CR-1-producing cell type. Morphological examination revealed an immature and invasive trophoblast profile in creta placentas, suggesting impairment of the trophoblast differentiation pathway. These findings provide important new insights into the pathophysiology of abnormal creta placentation and its gestational consequences.