We evaluated the role of changes in cytochrome P-450 2E1 (CYP 2E1) and lipid peroxidation in relation to development of severe liver injury in fish oil-ethanol-fed rats. The experimental animals (male Wistar rats) were divided into 5 rats/group and were fed the following diets for 1 month: corn oil and ethanol (CO+E) or corn oil and dextrose (CO+D), and fish oil and ethanol (FO+E) or fish oil and dextrose (FO+D). For each animal, microsomal analysis of CYP 2E1 protein, aniline hydroxylase activity, fatty acid composition, and conjugated dienes was conducted. Also, evaluation of severity of pathology was done for each rat. The mean +/- SD of the pathology score was significantly higher (p < 0.01) in the FO+E (6.0 +/- 1.3) group than in the CO+E group (3.0 +/- 0.5). No pathological changes were evident in the dextrose-fed controls. The CYP 2E1 protein levels (mean +/- SD) were significantly higher (p < 0.01) in the FO+E group (13.1 +/- 2.0) compared with the CO+E (4.7 +/- 1.2) and FO+D (1.8 +/- 0.5) groups. Higher levels of eicosapentaenoic and docosahexaenoic acids and lower levels of arachidonic acid were detected in liver microsomes from rats fed fish oil compared with corn oil. A significant correlation was obtained between CYP 2E1 protein and conjugated diene levels (r = 0.78, p < 0.01). Our results showing markedly increased CYP 2E1 induction and lipid peroxidation in the FO+E group provides one possible explanation for the greater severity of liver injury in this group.