Several lines of evidence suggest that macrophages play a key role in atherosclerotic plaque destabilization and rupture. Selective removal of macrophages from plaques via pharmacological therapy could therefore represent a promising approach to stabilize 'vulnerable', rupture-prone lesions. Yet, how macrophages can be eliminated from plaques without influencing other cell types, including smooth muscle cells (SMCs), is unknown. In the present study, we report that benzyloxycarbonyl-Val-Ala-DL-Asp(O-methyl)-fluoromethylketone (z-VAD-fmk), a caspase inhibitor with broad specificity, induces nonapoptotic cell death of J774A.1 and RAW264.7 macrophages, but not of SMCs. Cell death was characterized by bulk degradation of long-lived proteins, processing of microtubule associated protein light chain 3, and cytoplasmic vacuolization, which are all markers of autophagy. However, also necrosis occurred and the number of necrotic cells rapidly increased during z-VAD-fmk treatment. Primary mouse peritoneal macrophages were resistant to z-VAD-fmk mediated cell death, but unlike SMCs they underwent z-VAD-fmk mediated necrosis after pre-treatment with IFN-gamma. Further evidence indicated that the expression level of receptor interacting protein 1 (RIP1) mediates the sensitivity to z-VAD-fmk. Importantly, upon z-VAD-fmk treatment J774A.1 macrophages overexpressed and secreted several chemokines and cytokines, including tumor necrosis factor-alpha (TNFalpha). The combination of z-VAD-fmk and TNFalpha, but not TNFalpha alone, induced SMCs necrosis via a mechanism that required RIP1 expression. These results suggest that z-VAD-fmk, despite its selective cell death inducing capacity, would be detrimental for the stability of atherosclerotic plaques due to enlargement of the necrotic core, stimulation of inflammatory responses and indirect induction of SMC death.