Macrophages are thought to play an important role in the pathogenesis of atherosclerosis by mediating the oxidation of low-density lipoprotein (LDL). However, it is known that these cells show elevated glutathione levels after exposure to oxidized LDL. Here we demonstrate that this increase in the level of intracellular glutathione is due to synthesis de novo stimulated by oxidized LDL. Furthermore, inhibition of glutathione synthesis renders oxidized LDL cytotoxic to both monocytes and macrophages at a concentration well tolerated by untreated cells. The stimulation of cholesterol esterification in macrophages by low, non-toxic, concentrations of oxidized LDL is enhanced under conditions where glutathione synthesis is inhibited. These results suggest that the glutathione status of macrophages in the artery wall could be important in both controlling foam-cell formation and the detoxification of oxidized LDL.