The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109±0.016 mm²; ruptured, 0.192±0.009 mm²; P=0.0005), luminal occlusion (intact, 35.3±3.3%; ruptured, 57.7±1.9%; P<0.0001), the number of buried caps within the lesion (intact, 1.06±0.12; ruptured, 2.66±0.16; P<0.0001), fibrous cap thickness (intact, 4.7±0.6 μm; ruptured, 2.0±0.3 μm; P=0.0004), and lipid fractional volume (intact, 35.9±3.0%; ruptured, 50.7±2.2%; P=0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.