The aim of the present work was to analyze the effect of partial and total replacement of fish oil (FO) by a blend of vegetable oils on the health and antioxidant status of gilthead sea bream (Sparus aurata L.) fed primarily plant protein-based diets. The study included measurements of feed-borne contaminants, gene expression analyses of detoxifying and antioxidant pathways and measures of antioxidant and innate immune descriptors. Polybrominated diphenyl ethers (PBDEs) were almost undetectable in all diets, and the loading-charges of polychlorinated biphenyls (PCBs), dioxin-like PCBs, organochlorine pesticides (OCs), and polycyclic aromatic hydrocarbons (PAHs) were at trace levels decreasing their concentrations according to the level of FO replacement with vegetable oils (0%, 33%, 66%, and 100%). Hepatic detoxifying pathways were down regulated by FO replacement, and the hepatic transcription of cytochrome P450 1A1 and aryl hydrocarbon receptor 1 was significantly reduced in fish fed the 100% vegetable oil diet. Dietary intervention did not alter the hepatic expression of the recycling glutathione reductase, whereas glutathione peroxidase-1 and phospholipid glutathione peroxidase were either down- or up-regulated by total FO replacement. This suggests that vegetable oils prime the in situ repair of peroxidized phospholipids rather than the increased turnover of membrane phospholipids from the undamaged pool of cytosolic free fatty acids. The hepatic expression of non-enzymatic antioxidants (metallothionein, glucose regulated protein 75) was down regulated in fish fed 66% and 100% vegetable oil diets. Hepatic glutathione levels and total plasma antioxidant capacity were also lowest in fish fed high levels of vegetable oils, but the concurrent increase in the GSH/GSSG ratio was interpreted as an index of reduced oxidative stress. This redox balance agrees with the enhanced respiratory burst of blood leucocytes after phorbol myristate acetate stimulation in fish feed the 100% vegetable oil. Total plasma peroxidases and plasma alternative complement pathway were not affected by dietary treatment, whereas plasma lysozyme was significantly decreased in fish fed the 66% vegetable oil diet. Taken together, the results suggest that the health and the antioxidant status of gilthead sea bream was not damaged by high levels of FO replacement in eco-friendly diets, but both the scavenging and production of reactive oxygen species were modulated in concert by complex and nutritionally mediated readjustments. © 2009 Elsevier B.V. All rights reserved.