High concentrations of low-density lipoproteins (LDL) in the blood can lead to coronary heart disease, the primary cause of death in the Western hemisphere. A new treatment to reduce LDL levels is now being tested on rabbits, which are model animals for hypercholesteremia. The treatment involves using an immobilized enzyme within a bioreactor that is incorporated in an extracorporeal circuit. The enzyme modifies LDL to a form that is much more rapidly removed from the circulation. A mathematical model to describe LDL metabolism in the presence of the bioreactor was developed to give a better understanding of the biodistribution of modified LDL during and following treatment. A four-compartment model was developed on the basis of previous studies on human lipid metabolism, with the specific values of the constants taken from the experimental data on rabbits. A Macintosh II computer with a Stella II modeling program was used to simulate the treatment and to predict LDL levels over time given different values for initial enzyme activity, length of treatment, rate of enzyme denaturation, and other relevant parameters. The model provided a close fit with the experimental results for the change in total cholesterol. It confirmed the observed delay in the plasma cholesterol rebound level after the end of the extracorporeal treatment. One conclusion derived from both the experimental data and the model is that during the first 1.5 h, the limiting step for LDL removal is the rate at which modified LDL is taken up by the liver. However, bioreactor cessation becomes the limiting step in maintaining low LDL levels for an extended term. The study suggests that continuous modification of LDL, possibly using an implantable device, is required to maintain low levels of plasma LDL.