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Local hypoxia is a universal phenomenon in most solid tumors.The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established.However,the effect of acute systemic hypoxia (exposing the whole body to 10％ O2 environment) on cancer has not yet been investigated.In this study,we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC.Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice.Interestingly,the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight.Moreover,acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression.More importantly,the expressions of hypoxia response genes including hypoxia-inducible factor-1α,vascular endothelial growth factor,and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment.Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin.This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.