Abstract—Several studies suggest that macrophage death and subsequent lysis contribute to the development of advanced atherosclerotic lesions. Although oxidized LDL (OxLDL) is thought to contribute to lesion formation and induces macrophage apoptosis, the mechanisms underlying macrophage lysis have not been well defined. To determine if induction of apoptosis in human macrophages also promotes cell lysis, we studied caspase-3 activation by OxLDL and activating anti-Fas antibodies. We found that Fas-induced activation of caspase-3 does not promote macrophage lysis and caspase-3 activation is not required for OxLDL-induced macrophage lysis. OxLDL induces the formation of peroxides, but not superoxide, and decreases mitochondrial membrane potential. Scavengers of peroxyl radicals restore mitochondrial membrane potential and prevent macrophage lysis, implicating peroxyl radicals in both mitochondrial dysfunction and macrophage lysis induced by OxLDL. We conclude that macrophage death induced by OxLDL results in cell lysis, but it does not require activation of Fas or caspase-3. The full text of this article is available at http://www.circresaha.org.