The role of the spleen on the metabolism of lipids in cholesterol-fed rabbits was evaluated. Rabbits were divided into two groups: splenectomized and control (sham-operated) groups. After the operation, all rabbits were fed a 1% cholesterol diet for 12 weeks and the changes in serum lipids were observed. In a separate experiment, a study of the clearance of 125I-labeled lipoproteins, including beta-migrating very-low density lipoprotein (beta-VLDL), low density lipoprotein (LDL), and acetoacetylated-LDL, was carried out in both groups of rabbits. After cholesterol feeding, all rabbits showed marked hyperlipidemia; however, the splenectomized animals showed a significantly higher level of serum total cholesterol, triglycerides, and phospholipids together with a lower level of high-density lipoprotein cholesterol. A lipoprotein clearance study showed that beta-VLDL was cleared more slowly from the plasma of the splenectomized rabbits than of the controls fed a 1% cholesterol diet. Without cholesterol feeding, beta-VLDL was cleared more rapidly, and to a similar extent in both groups. The plasma clearance of either LDL or acetoacetylated-LDL did not differ between the two groups. These findings suggest that the spleen may play a role in catabolizing the excessive beta-VLDL in rabbits with dietary-induced hyperlipidemia.