Substantial　data　from　preclinical　studies　have　revealed　the　biphasic　effects　of　statins　on　cardiovascular　angiogenesis.　Although　some　have　reported　the　anti-angiogenic　potential　of　statins　in　malignant　tumors,　the　underlying　mechanism　remains　poorly　understood.　The　aim　of　this　study　is　to　elucidate　the　mechanism　by　which　simvastatin,　a　member　of　the　statin　family,　inhibits　tumor　angiogenesis.　Simvastatin　significantly　suppressed　tumor　cell-conditioned　medium-induced　angiogenic　promotion　in　vitro,　and　resulted　in　dose-dependent　anti-angiogenesis　in　vivo.　Further　genetic　silencing　of　hypoxia-inducible　factor-1　(HIF-1)　reduced　vascular　endothelial　growth　factor　and　fibroblast　growth　factor-2　expressions　in　4T1　cells　and　correspondingly　ameliorated　HUVEC　proliferation　facilitated　by　tumor　cell-conditioned　medium.　Additionally,　simvastatin　induced　angiogenic　inhibition　through　a　mechanism　of　post-transcriptional　downregulation　of　HIF-1　by　increasing　the　phosphorylation　level　of　AMP　kinase.　These　results　were　further　validated　by　the　fact　that　5-aminoimidazole-4-carboxamide　ribonucleotide　reduced　HIF-1　protein　levels　and　ameliorated　the　angiogenic　ability　of　endothelial　cells　in　vitro　and　in　vivo.　Critically,　inhibition　of　AMPK　phosphorylation　by　compound　C　almost　completely　abrogated　simvastatin-induced　anti-angiogenesis,　which　was　accompanied　by　the　reduction　of　protein　levels　of　HIF-1　and　its　downstream　pro-angiogenic　factors.　These　findings　reveal　the　mechanism　by　which　simvastatin　induces　tumor　anti-angiogenesis,　and　therefore　identifies　the　target　that　explains　the　beneficial　effects　of　statins　on　malignant　tumors.