The purpose of this study was to investigate the effect of eicosapentaenoic and docosahexaenoic acids on plasma lipids and lipoproteins, lipid peroxidation and antioxidant status in healthy humans. A total of 19 healthy volunteers consumed 6 g/day Maxepa® fish oil for 3 weeks (1.8 g n-3 fatty acids/day). At baseline and at day 21, we evaluated plasma lipoproteins, plasma and low-density lipoprotein fatty acids, lipid peroxidation markers (malondialdehyde concentration, low-density lipoprotein peroxidation in vitro), and the content of a number of antioxidants (reduced and oxidized glutathione in whole blood, plasma and erythrocyte glutathione peroxidases, plasma vitamin E and beta carotene). Plasma concentrations of total cholesterol, triglycerides, phospholipids, low-density lipoprotein cholesterol and low-density lipoprotein size did not differ significantly after 3 weeks of supplementation. Adding the fish oil to the diet increased the concentration of n-3 very-long-chain polyunsaturated fatty acids and decreased the concentration of n-6 fatty acid and oleic acid in plasma and low-density lipoprotein. Eicosapentaenoic and docosahexaenoic acid supplementation caused elevated values of the high-density lipoprotein cholesterol due to an increment of the high-density lipoprotein 2 fraction and reduced low-density lipoprotein peroxidation rate in vitro. However, we observed an imbalance between oxidizable substrates and antioxidants with an increased lipid peroxidation, whereas the content of reduced glutathione and beta carotene decreased without any variation in vitamin E. Association of antioxidants with n-3 PUFA could prevent lipid peroxidation and enhance the antiatherogenic effects of n-3 polyunsaturated fatty acids.