The aim of the present study was to analyze the frequency and mechanism of cell-death in atherosclerotic plaques with a recent history (< 6 months) of rupture. Atherosclerotic plaques were obtained from patients with symptomatic ipsilateral carotid stenosis > 70% diameter reduction undergoing carotid endarterectomy. In situ tailing and nick translation of fragmented DNA, agarose gel electrophoresis of plaque DNA and electron microscopy were used to identify cell death by apoptosis (programmed cell death) and oncosis. The mean number of cells containing fragmented DNA in the plaques was 12.7 +/- 3.5% (n = 15). Focal accumulations of cells with DNA fragmentation occurred in the fibrous cap, at sites of rupture, close to lipid deposits and necrosis and was always accompanied by the presence of inflammatory cells. Electrophoretic separation of DNA isolated from part of plaques, where the presence of DNA fragmentation had previously been demonstrated by in situ DNA nick translation, resulted in multiple ladders of 180-200 base pairs characteristic of apoptosis. Electron microscopic analysis revealed presence of cells with morphological signs of degeneration in a frequency even higher than that found by in situ nick translation. Some of these cells had a characteristic apoptotic appearance with condensed chromatin and cytoplasm, but the large majority of the cells had an ultrastructure typical for cells undergoing cell death by oncosis with membrane disruption and swollen, disintegrating organelles. Thus, although apoptosis clearly takes place in atherosclerotic plaques, oncosis appears to be a much more common mechanism for cell death.