The study was undertaken to determine whether eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), esterified in phospholipids (PL) as liposomes or in triglycerides (TG) as oil, exhibited comparable fates in liver lipids and whether these fates were associated with gene expressions related to fatty acid (FA) metabolism. PL and TG mixtures with close contents in EPA and DHA were administered to rats over 2 weeks. Most relevant events occurred after 3 days for both treatments. At that time, liposomes, compared with oil, increased the liver content in PL with a FA composition enriched in n-6 FA, comparable in DHA and much lower in EPA. Moreover, liposomes increased the activity and mRNA levels of carnitine palmitoyltransferase (CPT) I. In contrast, fish oil exerted opposite effects on CPT I and increased the genic expression of lipogenic enzymes. Liposomes, unlike fish oil, apparently increased the mRNA levels of acyl-CoA oxidase and the activity of the peroxisomal FA-oxidising system. Concomitantly, mRNA levels of hepatic lipoprotein receptors were increased with both diets, but intracellular proteins involved in free FA uptake and lipid synthesis were up-regulated only with liposome-treated rats. The quasi absence of EPA in hepatic PL of liposome-treated rats on the short term could result from increased beta-oxidation activities through metabolic regulations induced by more available free EPA and other PUFA.