Sudden cardiac death is one of the most frequent causes of death at high altitude. It has been reported that the intermittent normobaric hypoxia experienced by patients with obstructive sleep apnea may enhance the development of atherosclerosis. However, the effect of hypobaric hypoxia, which mimics the ambient air at high altitude, in the development of atherosclerosis has not been investigated.Twenty male ApoE-deficient mice, 8 weeks of age, were subjected to either control conditions or intermittent hypobaric hypoxia (IHH) for 8 weeks. Mice in the IHH group were exposed to a hypobaric chamber that replicated the hypobaric hypoxia conditions found at 4000 m altitude for 8 hours a day.IHH-exposed mice did not significantly differ from control mice in plasma lipid levels, including triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein. The hematoxylin and eosin-stained sections of the aortic root showed similar plaque size between the groups. However, IHH-treated mice exhibited significantly decreased plaque collagen content, a feature of atherosclerotic plaque stability. Additionally, matrix metalloproteinase (MMP)-9 protein expression was significantly increased, whereas tissue inhibitor of MMP (TIMP)-2 expression was decreased after exposure to IHH.IHH may promote atherosclerotic plaque instability in ApoE-deficient mice by changing the balance of MMPs and TIMPs.