Apoptosis or programmed cell death is a cellular suicide mechanism that frequently occurs in advanced human atherosclerotic plaques. Caspases, a family of cysteine proteases, have been identified as important effectors of the death machinery. In this study, we report strong caspase-2 immunoreactivity in foam cells of macrophage-origin around the necrotic core of advanced human atherosclerotic plaques. In contrast, smooth muscle cells (SMCs) and macrophages in the fibrous cap as well as endothelial cells, medial SMCs, and SMCs from mammary arteries are negative for caspase-2. Caspase-2-positive macrophages were isolated from human plaques by laser capture microdissection and were then analyzed by Western blotting. A single band of approximately 35 kd corresponding with the precursor of the short, anti-apoptotic isoform of caspase-2 (caspase-2S) could be identified. Treatment of human U937 macrophages with the DNA strand-breaking agents etoposide or camptothecin stimulated caspase-2S expression. Since atherosclerotic plaques contain a high number of DNA strand breaks, our results provide evidence for a survival factor in macrophage-derived foam cells of human atherosclerotic plaques that might be up-regulated in response to DNA damage.