ABSTRACT. We investigated the role of lipid peroxidation as the mechanism mediating copper toxicity in isolated rat hepatocytes and the modulating effect of vitamin E. Hepatocytes, isolated from rats fed diets containing deficient (E-), sufficient (E+), and excess (E++) amounts of vitamin E, were incubated with CuClz (0-2400 pM) for 150 min. Dose and time-dependent decreases in hepatocyte viability (determined by trypan blue exclusion and lactate dehydrogenase release) due to copper toxicity correlated with production of malonyldialdehyde in E-and E+ hepatocytes. However, malonyldialdehyde generation did not accompany copper toxicity in E++ cells. Copper toxicity was enhanced in E-compared to E+ and E++ hepatocytes as assessed by cell viability studies and ultrastructural plasma membrane bleb formation.