The effect of a short-term high cholesterol diet on thrombopoiesis and vascular ultrastructure was evaluated in rabbits. Six pairs of male litter-mate rabbits were randomized pairwise to feeding with either 2 g of cholesterol daily in addition to their normal diet or normal diet alone for 7 days. A significant 12-fold increase in median serum cholesterol (P less than 0.035) and an insignificant decrease in platelet count (P = 0.07) were found in the animals fed a high cholesterol diet. In these animals the total and cytoplasmic megakaryocyte size measured as planimetric areas in bone marrow sections were significantly decreased (P less than 0.035). No statistically significant difference in the megakaryocyte DNA content measured by flow cytometry in marrow suspensions enriched for megakaryocytes by density gradient centrifugation and centrifugal elutriation was observed between the cholesterol-fed animals and controls. Light microscopic, transmission and scanning electron microscopic examination of the aorta in both groups of animals showed a morphologically intact endothelium without any adhesion of blood-borne cells to the luminal surface. Transmission electron microscopic studies showed that cells with ultrastructural features resembling smooth muscle cells were present in the intima of the aortas of the animals on the high cholesterol diet, but not in control animals. A decrease in the size of bone marrow megakaryocytes and the occurrence of intimal smooth muscle cells are found in rabbits fed a high cholesterol diet for 7 days. These cellular events may be important features in early atherogenesis.