The study evaluated the effect of the traditional Chinese medicine rhubarb on the stability of atherosclerotic plaque. Atherosclerotic lesions were induced in rabbits through balloon injury with a high-cholesterol diet and then were divided into a control group, a rhubarb group and a simvastatin group. At week 24 recombinant-p53 adenoviruses were locally delivered to the atherosclerotic plaques. At week 26 plaque rupture was triggered by the intra-arterial Chinese Russell's viper venom and histamine. Serological, ultrasonographic, pathologic, immunohistochemical and gene expression studies were performed. The results showed that the incidence of plaque rupture in the rhubarb group and the simvastatin group was significantly lower than that in the control group (42.86% and 35.71% versus 80.00%, both p < 0.05). Serum TC, LDL-C (p < 0.05-0.01), IMT (both p < 0.01), PA (both p < 0.01), PB (%) (both p < 0.01) and the mRNA and protein expressions of TLR2, TLR4 and NF-kappaB (p < 0.05, 0.01, respectively) in the rhubarb group and the simvastatin group were significantly lower than those in the control group. In contrast, AIIc% (both p < 0.05) in the two treatment groups were significantly higher than those in the control group. These results suggest that rhubarb has antiatherosclerotic and plaque-stabilizing properties due to antiinflammation and lipid-lowering effects.