There is a great resemblance in the sequence of events that take place in the pathological development of intimal thickening, so called arteriosclerosis and the formation of intimal cushions in both the normal ductus arteriosus (DA) and the persistent ductus arteriosus (PDA). The human DA was used as a model to study the changes in the extracellular matrix during this process with immunohistochemistry. The formation of intimal cushions was studied in 4 normal fetal DA, 4 normal mature DA and 3 persistent DA. The process of intimal thickening in the fetus starts in the second trimester of pregnancy with an accumulation of glycosaminoglycans in the subendothelial region (SER), accompanied by separation of endothelial cells from the internal elastic lamina and followed by migration of smooth muscle cells into the subendothelial region. This phenomenon was also observed in the mature DA in the neonate, indicating that cushion formation is a continuous process. Intimal cushions had also developed in the persistent DA, although they were morphologically different from the cushions found in the normal mature DA. It was remarkable that two elastic lamellae could be distinguished: one at the original site on the borderline of intimal cushion and media and the other in a subendothelial position. The endothelial cells were firmly attached to this subendothelial lamina, which was wrapped in the basal lamina components laminin and type IV collagen. The main morphological difference between the normal mature DA and the persistent DA is the close relation between endothelial cells and the subendothelial elastic lamina, suggesting an altered elastin metabolism in the PDA. PGI2 synthase was increased in the wall of both the normal and persistent DA as compared with the aorta. It may be related to a role of PGI2 in the formation of intimal cushions.