PURPOSE: The purpose of this paper is to study molecular imaging of apoptosis and necrosis, two key players in atherosclerosis instability, using a multimodal imaging approach combining single photon emission computed tomography (SPECT), positron emission tomography (PET), and computed tomography (CT). PROCEDURES: Collar-induced carotid atherosclerosis ApoE knockout mice were imaged with 99mTc-AnxAF568 SPECT-CT to study apoptosis and sequentially with PET-CT following 124I-Hypericin (124I-Hyp) injection to visualize necrosis. RESULTS: SPECT depicted increased 99mTc-AnxAF568 uptake in both atherosclerotic carotid arteries, whereas our data suggest that this uptake is not merely apoptosis related. Although PET of 124I-Hyp was hampered by the slow blood clearance in atherosclerotic mice, 124I-Hyp was able to target necrosis in the atherosclerotic plaque. CONCLUSION: Both 99mTc-AnxAF568 and 124I-Hyp uptake are increased in atherosclerotic carotid vasculature compared to control arteries. While apoptosis imaging remains challenging, necrosis imaging can be feasible after improving the biodistribution characteristics of the probe.