Fetal trophoblast cells invade endometrial blood vessels and gain access to maternal blood within two days after the onset of blastocyst implantation in macaques. Soon thereafter, cytotrophoblast cells migrate well into the lumina of arteries and subsequently invade arterial walls. Using electron microscopy and light microscopy we investigated the interactions between invasive cytotrophoblast cells and the cellular and extracellular components in the walls of endometrial arteries. The placentas and adjacent endometrium of 22 macaques (GD 17 to term) were examined. Spiral arteries containing migratory cytokeratin-labeled cytotrophoblast cells were identified at all stages examined. Early modification of each artery showed that a plug of intraluminal cytotrophoblast cells temporarily filled the arterial lumen in the vicinity of the trophoblastic shell. Distal to this plug the group of cells tapered as a continuous mass, filling only a portion of the lumen. Endothelial cells were displaced from their basal lamina by closely apposed cytotrophoblast cell processes. Soon thereafter these processes penetrated the basal lamina and achieved contact with smooth muscle cells of the tunica media. As cytotrophoblast cells infiltrated the arterial wall they hypertrophied and secreted extracellular matrix, thereby differentiating into intramural cytotrophoblast. The patent lumen of the artery was reestablished concomitant with the migration of intraluminal cytotrophoblast cells through the arterial tunica intima and into the tunica media. The presence of clusters of cytotrophoblast cells in the arterial wall results in discontinuity of the tunica media and dispersion of the smooth muscle. The combined changes result in expanded circumferences of invaded arteries as well as diminished ability to contract. In portions of arteries adjacent to the trophoblastic shell cytotrophoblast usually occupied the entire perimeter and thickness of the artery wall, while in areas distal only a portion of the wall was invaded. Despite extensive arterial modification, evidence of cell death among the fetal and maternal tissues involved was rare. By later gestation only a few intraluminal cytotrophoblast cells were seen. Intramural cells were surrounded by a thick layer of matrix, but maintained contact with adjacent cells through cytoplasmic processes, some of which formed gap junctions. Maternal cellular and connective tissue elements were excluded from the cytotrophoblast-matrix pads and the cytotrophoblast cells retained attributes of glycoprotein producing cells to term. Spiral arteries were modified well into the spongiosum layer of the endometrium, and some were modified into the myo-metrium.