Chemical modification of lysine residues by acetoacetylation of the apoproteins of iodinated canine and human low density lipoproteins (LDL) and canine high density lipoproteins (HDL) resulted in a marked acceleration in the rate of removal of these lipoproteins from the plasma after i.v. injection into dogs. Clearance of the lipoproteins from the plasma correlated with their rapid appearance in the liver. Acetoacetylated canine 125I-LDL were essentially completely removed from the plasma within an hour, and > 75% of the activity cleared within 5 min. Reversal of the acetoacetylation of the lysine residues of the LDL restored to these lipoproteins a clearance rate essentially identical to that of control LDL. Identical results were obtained with modified human LDL injected into digs. At 10 min, when .simeq. 90% of the acetoacetylated human 125I-LDL had been removed from the plasma, 90% of the total injected activity could be accounted for in the liver. It was also possible to demonstrate an enhancement in uptake and degradation of acetoacetylated LDL by canine peritoneal macrophages in vitro. Acetoacetylation of canine 125I-apoE HDLc did not accelerate their rate of removal from the plasma but retarded their clearance. Control (native) apoE HDLc were removed from the plasma (64% within 20 min) and rapidly appeared in the liver (39% at 20 min). At the same time point, only 45% of the acetoacetylated apoE HDLc was cleared from the plasma and < 10% appeared in the liver. Acetoacetylation of the apoE HDLc did not enhance their uptake or degradation by macrophages. The rapid clearance from the plasma of the native apoE HDLc in normal and hypercholesterolemic dogs suggests that the liver may be a normal site for the removal of the cholesteryl ester-rich apoE HDLc. The retardation in removal after acetoacetylation of apoE HDLc indicates that the uptake process may be mediated by a lysine-dependent recognition system.