Lipoproteins (LP), isolated from human sera by column chromatography and density ultracentrifugation, were tested for their ability to inhibit macrophage (Mø)-mediated tumor cell destruction. None of the LP subclasses isolated by ultracentrifugation inhibited Mø-mediated cytolysis. Chromatography on a Sephadex G-200 column, prior to or following ultracentrifugation, resulted in the isolation of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) that prevented tumor cell destruction by Mø. High-density lipoprotein did not acquire the ability to inhibit Mø-mediated tumor cell killing under any condition. The acquisition of inhibitory activity by VLDL and LDL subclasses could be prevented by incorporation of EDTA and the bubbling of nitrogen gas into the chromatography buffer. These conditions inhibited the formation of lipid peroxides and thus prevented the formation of LP that inhibit Mø-mediated cytotoxicity. The mechanism by which oxidized LP prevents Mø from destroying tumor targets is not known. However, the mechanism does not appear to be related to a decrease in Mø viability. © 1984, Oxford University Press. All rights reserved.