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Objective To explore the anti-atherogenic activity and mechanism involved of ginsenoside derivative CK201 by ApoE-/- mouse and human umbilical vein endothelial cells (HUVECs). Methods In vivo experiment: 6-week-old male ApoE-/- mice(n=30) were randomly divided into 5 groups: the solvent control group, the model group, the ginsenoside compound K(CK) group, the atorvastatin calcium group and the CK201 group. Except the solvent control group, mice in other groups were fed high-fat diet. At the same time, mice in the CK group, the atorvastatin calcium group and the CK201 group were administrated intragastrically 3 mg/kg compound, respectively. The effect of CK201 and atorvastatin calcium on the formation of AS plaque was evaluated by aorta oil red O staining. The plasma levels of TC and TG were detected, and the effects of CK201 and atorvastatin calcium on blood lipid in mice were investigated. Western blot assay was used to analyze the effects of CK201 and atorvastatin calcium on the expression of inflammatory factors IL-6 and TNF-α of the aorta. The effects of CK201 and atorvastatin calcium on liver lipid accumulation were evaluated by HE and oil red O staining in liver sections. Liver and kidney function tests and blood routine tests of mice were performed to evaluate the effect of CK201 on related indicators. In vitro experiments: Western blot assay was used to analyze the effects of CK201 on the levels of IL-6 and TNF-α in HUVECs cells stimulated by palmitic acid. The effects of CK201 on the migration and recruitment of monocytes of HUVECs were analyzed by the scratch healing experiment of HUVECs cells and the adhesion experiment between monocytes (THP-1) and HUVECs cells. Results The CK201 group significantly inhibited the formation of atherosclerotic aortic plaques in ApoE-/- mice fed with high-fat diet, compared with the atorvastatin calcium group (plaque inhibition rate: 62.4% vs 26.6%, P < 0.05). The CK201 group had significantly reduced hepatic lipid accumulation, which had significantly better effect than those in the atorvastatin calcium group(P < 0.05). In the CK201 group, TC content in plasma was significantly decreased, the expressions of IL-6 and TNF-α in aorta were inhibited(P < 0.05), the expression of palmitic acid-stimulated inflammatory cytokines IL-6 and TNF-α in HUVECs cells was inhibited, the adhesion of THP-1 cells to HUVECs cells was reduced, and the migration of HUVECs cells was promoted(P < 0.05). In addition, the experimental dose of CK201 had no significant effect on the liver function and blood routine tests. Conclusion CK201, a ginsenoside derivative, has a significant anti-atherosclerosis effect, and the mechanism involved may be related to the reduction of plasma TC level, inhibition of aortic inflammation, inhibition of cell adhesion of monocyte and endothelial cells.