The results of this study indicate that when human VLDL or LDL is prepared under conditions allowing oxidation, such oxidation renders the molecular complexes highly toxic to human skin fibroblasts growing in culture. The cytotoxicity can be predicted by assaying for the presence of thiobarbituric acid-reacting substances on the lipoprotein. However, malondialdehyde, which reacts with thiobarbituric acid and is known to be injurious to cells, was not cytotoxic in the same experimental system when dissolved in culture medium or covalently bound to non-toxic LDL. The toxic agent(s) on oxidized LDL is(are) located in a lipid-extractable moiety. Since lipid peroxides and oxidized sterols can occur in vivo under various pathological conditions, the cytotoxicity of these lipoprotein-associated substances observed in vitro may be related to certain manifestations of these conditions.