Omega-3 fatty acids (FAs) reduce postprandial triacylglycerol (TG) concentrations. This study was undertaken to determine whether this effect was due to reduced production or increased clearance of chylomicrons. Healthy subjects (n ؍ 33) began with a 4-week, olive oil placebo (4 g/d) run-in period. After a 4-week wash-out period, subjects were randomized to supplementation with 4 g/d of ethyl esters of either safflower oil (SAF), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) for 4 weeks. Results for EPA and DHA were similar, and therefore the data were combined into one -3 FA group. Omega-3 FA supplementation reduced the postprandial TG and apolipoprotein B (apo B)-48 and apoB-100 concentrations by 16% ( P ؍ 0.08), 28% ( P Ͻ 0.001), and 24% ( P Ͻ 0.01), respectively. Chylomicron TG half-lives in the fed state were reduced after -3 FA treatment (6.0 ؎ 0.5 vs. 5.1 ؎ 0.4 min; P Ͻ 0.05), but not after SAF (6.9 ؎ 0.7 vs. 7.1 ؎ 0.7 min). Omega-3 FA supplementation decreased chylomicron particle sizes (mean diameter; 293 ؎ 44 vs. 175 ؎ 25 nm; P Ͻ 0.01) and increased preheparin lipoprotein lipase (LPL; 0.6 ؎ 0.1 vs. 0.9 ؎ 0.1 mol/h/ml; P Ͻ 0.05) activity during the fed state, but had no effect on postheparin LPL or hepatic lipase activities. The results suggest that -3 FA supplementation accelerates chylomicron TG clearance by increasing LPL activity, and that EPA and DHA are equally effective. There is growing evidence that abnormal postprandial lipemia is associated with coronary artery disease (1-5). Thus, reduction of postprandial triacylglycerol (TG) concentration may be cardioprotective. Studies have shown that chronic -3 fatty acid supplementation significantly lowers postprandial TG concentrations regardless of the type of fat in test meal (6-10). Since the consumption of test meals containing fish oil or vegetable oil produce similar rises in postprandial TG levels when subjects are consuming their usual background diets, fish oil itself is absorbed and cleared normally (11). There are only two mechanisms that can explain the reduced postprandial lipemia of chronic -3 fatty acid administration: slowed chylomicron secretion into the circulation or faster chylomicron clearance.Several investigators reported that -3 fatty acids do not enhance lipoprotein lipase (LPL) or hepatic lipase (HL) activity measured in vitro in human postheparin plasma (11)(12)(13)(14). It has also been shown that clearance of an intravenous bolus of lipid emulsion was not enhanced by fish oil feeding despite a reduction in the fasting TG concentration (9). On the other hand, others reported that -3 fatty acid supplementation increased pre-(15) and postheparin (16) LPL activities. As regards slowed secretion, since -3 fatty acids retard hepatic secretion of VLDL TG (17), they might have the same effect on intestinal chylomicron secretion.The objective of this study was to determine the extent of and mechanism responsible for reduced postprandial lipemia following supplementation with eicosapentaenoic acid (EPA) an...