Background--Atherosclerotic plaque rupture and thrombosis are the main cause of acute coronary syndrome. In the present study, we investigated whether ultrasound imaging and inflammatory parameters are predictive of plaque rupture in a newly established animal model. Methods and Results--We developed a rabbit model for plaque rupture by locally delivering recombinant-p53 adenovirus to plaques in rabbits fed a high-cholesterol diet for 10 weeks and plaque rupture was triggered using Chinese Russell's viper venom and histamine. We found that 81.1% rabbits transfected with p53 (n=37) had the ruptured plaques, which was significantly higher than the rabbits transfected with the control vector (26.3%, n=38, P<0.001). Among measured biomarkers, high sensitive C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly different between rabbits with and without ruptured plaques. Using the high frequency duplex and intravascular ultrasound imaging techniques, we obtained a list of parameters. With the multivariate logistic regression model, we identified that plaque eccentric index, plaque area, hsCRP and corrected integrated backscatter intensity were significant predictors of plaque rupture with odds ratios as 7.056 (95%CI:1.958~25.430), 1.942 (95%CI: 1.058~3.564), 1.025 (95%CI: 1.007~1.043) and 0.856 (95%CI: 0.775~0.946), respectively. Conclusions--Localized p53 over-expression technique induces plaque rupture and combined measurement of ultrasound and biochemical markers is a valuable tool in predicting plaque rupture.