In cholesterol-fed rabbits the extent of monocyte involvement in atherogenesis may be influenced by the level of circulating leukocytes during hypercholesterolemia. We characterized the leukocytosis in rabbits fed either a 0.25% or a 0.1% cholesterol-enriched diet (0.25% or 0.1% rabbits, respectively). Circulating leukocytes were elevated by 1 week of feeding, and the elevation was sustained for at least 30 weeks. Differential counts were unchanged. Immature leukocytes were not seen, indicating that the leukocytosis was not due to premature release of bone marrow cells. Animals were free of bacterial or parasitic disease; selected rabbits with leukocytosis had normal body temperatures. Spleen weights averaged at least 100% higher in 0.25% rabbits but did not show histological evidence for hematopoiesis that could account for the leukocytosis. At approximately 22 weeks there was a second rise in leukocytosis in bilirubinemic 0.25% rabbits, suggesting that in the late stages of hypercholesterolemia, leukocytosis is related to liver failure. Cholesterol-fed rabbits also showed thrombocytosis. Existing leukocytosis and hypercholesterolemia were reversed to pretreatment levels by switching the rabbits to chow diets. In bone marrow from 0.25% rabbits, the mean number of cells per gram was greater (p less than 0.05) than that from normocholesterolemic rabbits. In 0.25% rabbits, the fraction of blood mononuclear cells showing phagocytosis of immunoglobulin G-coated red blood cells did not differ from that of controls, suggesting an unchanged population of these cells with regard to Fc and phagocytic function during hypercholesterolemia. These data suggest an effect (direct or indirect) of hypercholesterolemia on the production of leukocytes in the bone marrow and/or on the circulation kinetics of leukocytes in the blood.