Aim To investigate the effect of aminolaevulinic acid (ALA)-mediated sonodynamic therapy (SDT) on atherosclerosis plaque. Methods The rabbit atherosclerotic model was established by balloon denudation and an atherogenic diet. The metabolism and distribution of protoporphyrin Ⅸ (PpⅨ) in the plaque were detected by fluorescence microscopy and fluorescence spectrometry at 0,1, 2,3, 4,5 and 6 hours after intravenous injection of ALA (n=3). Animals were randomly divided into control group and SDT group. Apoptosis and macrophage content were detected by TUNEL and immunohistochemistry at 6,2, 24 and 72 hours (n=7) after SDT treatment, and high-frequency ultrasound, pathology and immunohistochemistry were performed at 1 week after SDT treatment. Results Two hours after ALA injection, the content of PpⅨ in plaques reached a peak and mainly distributed in the areas of macrophages. Compared with the control group, the apoptosis of plaque cells increased by 3.1,3.8,7.5 and 4.0 folds at 6,2, 24 and 72 hours after SDT treatment, and the content of macrophages decreased by 45% and 67% at 24 and 72 hours after SDT treatment, and the stenosis rate of femoral artery diameter decreased by 14% at 1 week after SDT treatment. Compared with the control group, the plaque area of SDT group decreased by 38%; the lumen area increased by 86%; the content of lipid, macrophage, proliferative cells, IL-1 beta and TNF-alpha decreased by 64%, 71%, 76%, 62% and 60% respectively; and the content of collagen increased by 117%. Conclusions ALA-PpⅨ is mainly distributed in intraplaque macrophages, SDT induces macrophages apoptosis, and changes the components of plaque to promote plaque stability and reduce the size of plaque. SDT is a potential noninvasive method for the treatment of atherosclerotic plaques.