Selective chemical modification of lysine residues of lipoproteins by acetoacetylation dramatically altered the metabolism of the lipoproteins without significantly altering other physical or chemical properties. Modification of 30-60% of the total lysine residues of iodinated rat or human low-density lipoproteins (¹²⁵I-LDL) resulted in a rapid removal of these acetoacetylated lipoproteins from the plasma of rats. Within minutes after intravenous injection into intact rats, greater than 80% of the total injected dose disappeared from the plasma. The rapidly cleared acetoacetylated LDL appeared in the liver, and within 6-30 min as much as 50-80% of the total injected dose of modified LDL could be accounted for in the liver. Furthermore, it was possible to demonstrate in the isolated perfused rat liver that the Kupffer cells were responsible for the lipoprotein uptake. Human high-density lipoproteins (HDL₃) were also rapidly removed from the plasma after acetoacetylation. In striking contrast, acetoacetylation (30-60%) of two E apoprotein-containing lipoproteins (rat HDL₁ and dog HDL_c) retarded their removal from the plasma. The accelerated removal of modified LDL and HDL₃, in contrast to the retarded removal of modified HDL₁ and HDL_c, suggests that the recognition and removal process is specific for a property acquired by only certain lipoproteins after acetoacetylation. Moreover, these results suggest that lysine residues of the E apoprotein may play a functional role in the recognition process for the normal clearance of HDL₁ and HDL_c, a process that is interfered with after acetoacetylation.