A light and transmission electron microscopic study was performed on 67 ductus arteriosus (DA) specimens from rabbits (31 days normal gestation period) ranging in age from 21 days of gestation to 4 days after birth. Some fetuses were permitted to breath before sampling, while others were not. The aorta and pulmonary trunk served as controls. The objectives of the study were to identify the earliest cellular alterations leading to closure of the DA, to study in detail the sequence of cellular changes in closure of the DA, and to correlate these observations with what is known about the physiological factors involved in closure of the DA. Changes in the architecture of the DA wall were seen as early as on the twenty-sixth day of gestation and involved the appearance of increased numbers of radially or longitudinally reoriented smooth muscle cells in the intima and fragmentation of the internal elastic lamina. The progress of these changes continued and intensified until the end of gestation. At that stage the inner one-half of the medial smooth muscle cells was reoriented, and the lumen was significantly reduced by a greatly expanded intima which often contained many intercellular “ghost bodies.” Very few mitoses were seen during DA closure, especially during 29 to 31 days of gestation. It is concluded that cellular changes involved in closure of the DA of the rabbit fetus begin far in advance of birth and breathing. These cellular changes are highly analogous to those which occur in the early pathogenesis of arterial intimal fibromuscular lesions. Closure of the DA, therefore, seems to afford an excellent, natural model for study of key cellular events involved in the production of arterial fibromuscular lesions.