Aim To observe the effect of salidroside on atherosclerosis of apolipoprotein E gene knockout mice （ApoE^－/－） with intermittent hypobaric hypoxia, so as to illuminate the role of salidroside on atherogenesis. Methods Thirty eight-week-old male ApoE^－/－ mice were randomized into normobaric normoxic group （control group）, intermittent hypobaric hypoxia group （IHH）, hypobaric hypoxia＋salidroside group （intervention group） for 12 weeks. Mice in IHH group and intervention group were exposed to a hypobaric chamber mimicking the hypobaric hypoxia condition on an altitude of 5000 m for 8 hours every day, each group was fed with the same general diet, the intervention group was given salidroside 30 mg/（kg·d）, oral gavage, while the control group and IHH group were administered distilled water. Then fasting blood glucose （FBG） and plasma lipid levels were measured, paraffin sections of mice aorta roots were made. The aorta atherosclerotic lesion area and plaque collagen content were meassured by HE staining and Masson staining. Matrix metalloproteinase-2 （MMP-2） and MMP-9, tissue inhibitor of metalloproteinase-2 （TIMP-2） protein expression were analyzed by Western blot. Results The three groups did not statisticly differ in FBG and plasma lipid levels （P>0.05）. Compared with control group, atherosclerotic plaque area were increased significantly （P<0.01）, whereas plaque collagen content were increased in IHH group （P<0.01）. Compared with IHH group, plaque area and the protein expression of MMP-2 and MMP-9 were decreased significantly （P<0.01）, whereas plaque collagen content and the protein expression of TIMP-2 were increased in salidroside intervention group （P<0.01）. Conclusion Salidroside attenuates atherosclerosis and enhances plaque stability in ApoE^－/－ mice of IHH. The mechanism is in connection with salidroside increased plaque collagen content.