Background & aims: Intake of n-3 fatty acids can reduce both fasting and postprandial triglyceride (TG) concentrations in humans as well as in experimental animals, but the mechanisms by which this occurs are not completely known. We investigated in mice the effects of dietary fish oil (a source of n-3 fatty acids) on endogenous TG synthesis and exogenous TG-rich particle removal. Methods: C57 BL/6J mice were fed for 4 months with three types of high-fat diets (18% fat wt/wt) soy oil, fish oil and a mixture of soy oil and fish oil (soy/fish) (5:1 wt/wt), and a chow diet with 6% fat from soy oil (wt/wt) served as a control. Plasma TG and apolipoprotein B (apoB) concentrations and lipoprotein lipase (LPL) activity were measured. Triton WR 1339 was used to assess hepatic synthesis of very tow density Lipoprotein, and intravenous injection of chylomicron-like lipid emulsions was conducted to determine the effects of dietary fish oil n-3 fatty acids on exogenous TG clearance. Results: Both fish and soy/fish oil diets reduced plasma TG levels in fed and fasted states compared to soy oil alone. Plasma pre- and post-heparin LPL activities were significantly higher with fish and soy/fish oil diets than soy oil diet in fed mice. No differences in plasma TG levels and LPL activity were shown among groups of fish oil, soy/fish oil and normal chow diets. Levels of hepatic TG and apoB synthesis were 30-50% and 42% lower in mice fed with the fish oil diet compared to the other three diets. In addition, compared to soy oil diet, fish oil feeding significantly increased blood clearance of chylomicron-like lipid emulsions by 21-26%. Conclusions: Our data suggest that reduced endogenous TG synthesis, increased LPL activities and more rapid blood clearance of TG-rich particles all distinctly contribute to the TG-lowering effects of fish oil n-3 fatty acids. (C) 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.