Model-based compartmental analysis was used to interpret data on temporal changes in plasma triglyceride (TG) response to a chronic infusion of chylomicrons (CM) in the rat. Male rats were fed purified diets which varied in fat load [L = 10% (w/w), H = 30%] and P/S ratio (P = 4.6, S = 0.2). Lymph CM isolated from donor rats which were absorbing the P or S fat were infused into recipients for 8 h on 3 consecutive days: on d 1 and 3, CM infusion rate reflected the fat content of the previous diet and on d 2, the other load; the infusion replaced dietary fat. Serial plasma samples from each period were analyzed for TG concentration; TG distribution in plasma lipoproteins and liver lipids was measured after d 3. To describe observed group average data, a compartmental model was developed using the Simulation, Analysis and Modeling computer program. Two compartments were needed in plasma (CM vs nonCM TG); each had 2 outputs: removal of TG-fatty acids by lipoprotein lipase (LPL) and uptake of remnant lipoproteins by the liver. After a delay in the liver, there were 3 fates for TG-derived fatty acids: oxidation, retention, or secretion in very low density lipoproteins. Simulation of changes in the rate constant for total CM TG turnover indicated that the basal level of LPL rose rapidly and dramatically in response to TG infusion; the rise was higher for H vs L. After 3-5 h, apparent LPL activity decreased. Simulation of the rate of CM TG turnover indicated that the turnover rate rose immediately after infusion began to levels higher than the infusion rate, and then came into a slight negative balance. Although the observed data could be qualitatively described based on current understanding of TG metabolism, application of model-based compartmental analysis generated testable hypotheses about quantitative aspects of the system dynamics.