BACKGROUND: Atherosclerosis is the pathological basis of many cardiovascular and cerebrovascular diseases. Yiqi Tongmai Fang can significantly improve atherosclerosis in patients, but the metabolic spectrum and mechanism underlying the intervention of atherosclerosis using Yiqi Tongmai Fang are still incomplete. OBJECTIVE: To explore the possible mechanism of Yiqi Tongmai Fang in the treatment of atherosclerosis. METHODS: Thirty-six male C57/B6J mice were selected, 6 of which were used as normal controls and given normal diet for 12 weeks. The remaining 30 ApoE-/- mice were randomly divided into model group, low-, medium- and high-dose Yiqi Tongmai Fang groups and atorvastatin group, with 6 mice in each group, and then were fed with high fat diet combine with intragastrical administration of sodium chloride, low-, medium- and high-dose Yiqi Tongmai Fang (0.39, 0.78, 1.56 g/kg per day) and atorvastatin (2.6 mg/kg per day), respectively. Serum and aortic tissue were collected after 12 weeks. The pathological changes of the aorta and vascular stenosis were observed by vascular histopathological section. The serum samples were analyzed by ultrahigh performance liquid chromatography-mass spectrometer for high-throughput target metabolomics, to screen different amino acids between groups. RESULTS AND CONCLUSION: In terms of morphology, vascular pathological injury and stenosis were significantly improved in the Yiqi Tongmai Fang groups compared with the model group. In terms of serum amino acid metabolism, the levels of seven amino acids were significantly changed in the Yiqi Tongmai Fang group compared with the normal control group, including the increased levels of L-Glutamic acid, L-Tyrosine, L-Aspartate, L-Lysine and L-Valine, and the decreased levels of L-Arginine and 3-methyl-L-histidine. Yiqi Tongmai Fang could regulate the levels of different amino acids and high-dose Yiqi Tongmai Fang could regulate the most metabolites. Overall, these findings indicate that Yiqi Tongmai Fang can delay the progression of atherosclerosis and its mechanism may be related to the regulation of amino acid metabolism. Moreover, high-dose Yiqi Tongmai Fang has the most significant effect. [ABSTRACT FROM AUTHOR]