Dietary triglycerides containing predominantly poly-unsaturated fatty acids (PUFAs) are known to reduce plasma total and low density lipoprotein (LDL) cholesterol concentrations relative to triglycerides containing predominantly saturated fatty acids. However, there is little information regarding the independent effects of individual n-6 and n-3 PUFAs on LDL metabolism. The present studies were therefore undertaken to examine the effects of individual n-6 (linoleic acid) and n-3 (alpha-linolenic, eicosapentaenoic, and docosahexaenoic acid) PUFAs on plasma lipid levels and on the major transport processes that determine plasma LDL concentrations. Rats were fed a semisynthetic cholesterol-free diet supplemented with 4% (by wt) linoleic, alpha-linolenic, eicosapentaenoic, or docosahexaenoic acid for 2 weeks. Dietary eicosapentaenoic and docosahexaenoic acids lowered plasma triglyceride concentrations by 62% and 52%, respectively, and lowered plasma cholesterol concentrations by 54% and 43%, respectively. In contrast, dietary linoleic and alpha-linolenic acids had relatively little effect on plasma triglyceride or cholesterol concentrations. Dietary eicosapentaenoic and docosahexaenoic acids increased hepatic LDL receptor activity by 72% and 58%, respectively, and reduced the rate of LDL cholesterol entry into plasma by 36% and 30%, respectively. As a consequence plasma LDL cholesterol concentrations fell by 60% in animals fed eicosapentaenoic acid and 54% in animals fed docosahexaenoic acid. In contrast, these parameters of LDL metabolism were not significantly altered by dietary linoleic or alpha-linolenic acids. Thus, eicosapentaenoic acid and docosahexaenoic acid (the two major n-3 PUFAs present in fish oil) were equally effective in reducing the rate of LDL formation and stimulating hepatic LDL receptor activity, and were much more active in this regard than their parent compound (alpha-linoleic acid) or linoleic acid.