Aim To explore the effect of the compatibility of Alisma and Atractylodes on relieving atherosclerosis(As) in ApoE－/－mice and the correlation with reverse cholesterol transport. Methods ApoE－/－ mice were fed with a high-fat diet to construct an animal model of As and treated with Alisma and Atractylodes. The wall thickness, lumen diameter of common carotid artery were measured by ultrasound. HE staining was used to observe the morphology of the artery, and lipid deposition in the liver was observed by oil red O staining. Inflammatory cytokines such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), matrix metalloproteinase-2(MMP-2)were test by ELISA,and matrix metalloproteinase-9(MMP-9) and blood lipid components serum total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL) and high density lipoprotein(HDL)were analyzed by automatic biochemical analyser. Western blot was used to quantify the expression of silent information regulator protein 1(SIRT1), liver X receptor α(LXRα), ATP-binding cassette transporter A1(ABCA1)and scavenger receptor class B type Ⅰ (SR-BⅠ)in the ApoE－/－ mice liver. Results The compatibility of Alisma and Atractylodes not only significantly repressed the wall thickness, lumen diameter of the common carotid in ApoE－/－ mice, but also reduced the deposition of lipids in the ApoE－/－ mice liver. Treatment with Alisma decoction caused a drop in serum MMP-2, MMP-9, TNF-α, IL-1β, TC, TG, LDL and increase in serum HDL. The expression of SIRT1, LXRα, ABCA1 and SR-BⅠ were markedly up-regulated in the ApoE－/－mice liver treated with Alisma and Atractylodes. Conclusion It was suggested that the compatibility of Alisma and Atractylodes promoted reverse cholesterol transport to reduce liver lipid deposition, suppressed inflammation and improved the morphology of artery via SIRT1-LXRα-ABCA1/SR-BⅠ pathway. It exerted the protective effect in the occurrence and development of As.