Atherosclerosis is a metabolic and chronic inflammatory disease caused by deposition of lipoproteins in arteries. However, the diagnostic drug and the mechanism for this vascular disease are less studied. In the present study, atherosclerosis model was developed using apolipoprotein E-deficient mice that was treated with long-term high-fat food and chronic stresses. Xiaoyaosan (XYS) and glucocorticoid receptor (GR) antagonist RU 38486 were orally administrated to the mice. The change of aortic root vessels was observed by histological analysis. The results indicate that high-fat food coupled with chronic stress induced atherosclerosis in mice model, with plaque formation in the entire aortas foam cells and macrophage infiltration in aortic tissues. However, XYS granules inhibited the development of atherosclerotic lesion, with down-regulation of GC, TC, TG, HDL-C, ox-LDL, LDL-C, IFN-γ, IL-6, IL-1β, and TNF-α measured by ELISA method; XYS inhibited the expressions of GR, CD36, HSP27/60/90, and induced ABCA1 in atherosclerotic mice, which was measured by qPCR and Western blot, which showed similar effect as positive control RU 38486 did. The interaction between HSP90-GR complexes and CD36 was validated in atherosclerotic mice. Our results inferred that the HSP/GR complex-mediated CD36 axis was involved in the regulation of atherosclerosis development in mice verified by Co-IP assay, EMSA, and Chip-PCR. These findings not only provide the potential therapeutic value of Xiaoyaosan for atherosclerotic vulnerable plaque but also brought forth a novel strategy for preventing the formation and treatment of atherosclerotic vulnerable plaques through the elucidated mechanism of XYS on vulnerable plaque. AJTR Copyright © 2019.