Arterial stiffness has been associated with increased cardiovascular risk. We previously showed that arterial stiffness promotes both the progression of atherosclerosis and a more unstable plaque phenotype in apolipoprotein E (ApoE)- deficient mice with a mutation in the fibrillin-1 gene. In this study, we aimed to investigate whether these mice are suitable as an animal model for plaque rupture. Mice with a mutation (C1039G+/­) in the fibrillin-1 gene, leading to fragmentation of the elastic fibers, were crossbred with ApoE-deficient mice. At six weeks of age, female ApoE-/- Fibrillin-1 +/­ and ApoE-/- Fibrillin-1 +/+ (control) mice were fed a western type diet for up to 52 weeks. Between 13 and 27 weeks (average 17 weeks) of a Western type diet, 75% (12 out of 16) of ApoE-/- Fibrillin-1 +/­ mice died suddenly, which was mostly preceded by head tilt and/or motor problems (loss of orientation and balance). In contrast, mortality was not seen in the control group (0 out of 15 mice at 52 weeks). Magnetic Resonance Imaging showed the presence of one or more brain infarctions in all ApoE-/- Fibrillin-1 +/­ mice, whereas only one control mouse displayed a single brain infarct (p <0.001). Brain lesions were characterised by the presence of foam cells and cholesterol clefts and stained positively for neutral lipids, smooth muscle cells and macrophages, indicative of cerebral embolization of plaque material after rupture. ApoE-/- Fibrillin-1 +/­ mice seem to be a promising animal model for plaque rupture and stroke.