BACKGROUND For a long time, our major understanding of the spleen is to function as a blood filter for the removal of aged erythrocytes and circulating microorganisms. Splenectomy, therefore, has been widely performed in case of trauma and a variety of hematologic disorders. Although some studies have indicated an increased rate of developing hyperlipidemia and atherosclerotic cardiovascular diseases in splenectomized patients, our recognition of the splenic regulation on lipid metabolism and atherogenesis is still lacking. Here we explored this issue in Apoe deficient (Apoe-/-) mice fed on an atherogenic diet containing 0.5% cholesterol and 20% fat. METHODS 7-week-old male Apoe-/- mice were randomly divided into splenectomy group and sham operation group. After 1-week recovery from the surgery, mice were subjected to the atherogenic diet for the next 8 weeks. RESULTS The atherogenic diet induced a severe hypercholesterolemia (about 1500 mg/dl), steatohepatitis and accelerated atherogenesis in the Apoe-/- mice. Splenectomy, compared to sham operation, did not alter plasma lipid levels or lipoprotein profiles; it also did not alter hepatic or adipose lipid deposition. Meanwhile, splenectomy did not alter atherosclerotic plaque burden or composition; it also did not alter aortic gene expression associated with macrophage inflammatory responses. CONCLUSIONS Our data suggested that splenectomy had no significant impacts on lipid metabolism and atherogenesis in Apoe-/- mice fed on a severe atherogenic diet.