Apolipoprotein (apo) E is a 299-amino acid glycoprotein that serves a number of functions in lipoprotein metabolism. Apo E binds to the triglyceride-rich lipoproteins (TRL), very-low-density lipoprotein (VLDL), and chylomicrons, as they are lipolyzed, mediating their removal from plasma via lipoprotein receptors. Apo E is also found associated with high-density lipoprotein (HDL) and has been suggested to play a role in reverse cholesterol transport. Studies on the kinetic behavior of apo E from the TRL and HDL fractions provide insights into the metabolic relationships between TRL and HDL in vivo. We sought to develop a compartmental model that can be used for analysis of kinetic data in studies on the metabolism of TRL and HDL apo E. Using radioactive tracers, it has been previously observed that, in some instances, a portion of VLDL apo E that is removed from plasma subsequently reappears in VLDL. Four multicompartmental models were considered that could account for this type of behavior: model A, in which there is transfer of apo E from HDL to VLDL; model B, in which there is a bidirectional extravascular exchange; model C, in which there is removal and subsequent reintroduction of TRL apo E into plasma; and model D, in which there is secretion of TRL apo E into plasma directly and via an extravascular pathway. Models C and D provided the best fit to the experimental data. While no physiologically plausible analog to model C could be found, an extravascular delay, analogous to newly secreted apo E that enters the lymphatic system before appearing in plasma, was postulated for model D. It was this model that was used to analyze kinetic data from metabolic studies of apo E. The model was able to provide a satisfactory fit to kinetic data in studies in which subjects were given a primed-constant infusion of 2H3-leucine. It was determined that TRL apo E from the six subjects studied had a mean residence time of 0.11 +/- 0.05 days and a mean production rate of 10.6 +/- 7.2 mg/kg/d, while HDL apo E had a mean residence time of 2.96 +/- 0.99 days and a mean production rate of 0.07 +/- 0.07 mg/kg/d. We conclude that this model describes a potential pathway for the metabolism of a portion of apo E in plasma and can be used to calculate the residence time and production rate of TRL and HDL apo E under a variety of conditions.