Context: Dysregulated chylomicron metabolism may account for hypertriglyceridemia and increased risk of cardiovascular disease in obese subjects. Supplementation with ω-3 fatty acid ethyl ester (FAEE) decreases plasma triglyceride. However, its effect on postprandial chylomicron metabolism in obese subjects on a weight-loss diet has not yet been investigated. Objective: We aimed to examine the effect of ω-3 FAEE supplementation on apolipoprotein (apo) B-48 kinetics in obese subjects on a weight-loss diet. Design, Setting, and Patients:Wecarried out a 12-week, randomized trial of a hypocaloric diet plus 4 g/dω-3 FAEE supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) (n= 13) compared with a hypocaloric diet alone (n = 12) on postprandial apoB-48 kinetics in obese subjects after ingestion of an oral load. The apoB-48 kinetics were determined using stable isotope tracer kinetics and multicompartmental modeling. Outcomes Measures:Weevaluated plasma totalandincremental apoB-48 0- to 10-hour area under the curves (AUCs) as well as apoB-48 secretion and fractional catabolic rate. Results: Weight loss with or withoutω-3 FAEE supplementation significantly reduced body weight, total fat mass, homeostasis model assessment score, fasting triglyceride concentration, postprandial triglycerideAUC,andincreased plasma high-density lipoprotein cholesterol concentration (P<.05 in all). Compared with weight loss alone, weight loss plus ω-3 FAEE significantly (all P <.05) decreased fasting triglyceride (-11%), apoB-48 (-36%) concentrations, postprandial triglyceride (-21%), and apoB-48 (-22%) total AUCs, as well as incremental postprandial triglyceride AUCs (-32%). The ω-3 FAEE also significantly decreased apoB-48 secretion in the basal state, without a significant effect during the postprandial period (3-6 hours). The fractional catabolic rate of apoB-48 increased with both interventions with no significant independent effect of ω-3 FAEE supplementation. Conclusion: Addition ofω-3FAEEsupplementation to amoderateweight-loss diet in obese subjects can significantly improve chylomicron metabolism by independently decreasing the secretion of apoB-48. Copyright © 2014 by the Endocrine Society.