The cellular origin and development of radiation-induced atheromatous plaques in the carotid artery of the hypercholesterolemic rabbit have been studied morphologically from a few hours post-irradiation up to several weeks later. As early as 8 h following local X-irradiation (500 or 1,000 rad) mononuclear cells, presumably blood monocytes, enter the subendothelial space. The cells have disappeared again 10 days post-irradiation in normocholesterolemic animals. In irradiated hypercholesterolemic animals, however, the invading mononuclear cells transform into lipophages and become so-called foam cells, visible from the second day post-irradiation. The number of lipophages increases with time resulting in plaques of about 5-10 cell layers after 20 days. From 20 days post-irradiation onwards smooth muscle cells enter the plaque by migrating from the tunica media through the fenestrations of the lamina elastica interna. Smooth muscle cells are found to contain less lipid vacuoles than monocyte-derived lipophages. At 30 days post-irradiation the smooth muscle cells have formed parallel layers in the luminal side of the plaque encapsulating an inner core of foam cells and other material. The morphology of the plaque at 30 days post-irradiation is similar to that reported for advanced plaques developing in rabbits by mere cholesterol feeding over a relatively long period. In irradiated normocholesterolemic and in non-irradiated hypercholesterolemic rabbits plaques are not observed in the carotid arteries during the experimental period. The early involvement of blood monocytes has been separated from the later role of medial smooth muscle cells in radiation-induced plaque formation. The results suggest that the underlying process in this lesion may be understood in terms of a sterile inflammation, complicated by an immediate fatty degeneration and followed by repair phenomena. The combination of hypercholesterolemia and ionizing radiation may serve as a useful experimental model for further studies in various animal species on why and how plaques originate, develop or regress and how they could possibly be prevented. The relevance of the results to radiotherapy in humans is mentioned briefly.