Introduction: Tissue factor pathway inhibitor-2 (TFPI-2) is a member of the Kunitz-type family of serine protease inhibitors, which inhibits several matrix metalloproteinases activity involved in extracellular matrix degradation. Studies have shown low TFPI-2 expression in the shoulder regions of atherosclerotic plaques. But studies evaluating its role in the progression of atherosclerotic plaque are scarce. Vascular smooth muscle cells (VSMCs) are important components of atherosclerotic plaques and oxidized low density lipoprotein (ox-LDL) is an important detrimental factor of atherosclerosis. The aim of this study is to elucidate the effect of TFPI-2 on smooth muscle cell proliferation and migration induced by ox-LDL. Methods: Retroviruses expressing human TFPI-2 were constructed. Cell proliferation was determined by CCK-8 assay. Cell apoptosis was analyzed by double staining of FITC-Annexin V and propidium iodide. Cell migration was studied through a Transwell chamber and with a scratch-wound assay. The matrix metalloproteinase-2 and −9 activities were analyzed by gelatin zymography. Phosphorylation of FAK was analyzed by western blot. Results: TFPI-2 over-expression of mRNA and protein was confirmed in infected cells. CCK-8 assay showed that TFPI-2 inhibit VSMCs proliferation induced by ox-LDL while without cytotoxicity to VSMCs. Transwell and scratch wound assay confirmed TFPI-2 over-expression can inhibit VSMC migration. Zymography assay showed that TFPI-2 can inhibit MMP-2, 9 activity induced by ox-LDL. Western blot assay showed TFPI-2 can inhibit cyclinD1 expression and FAK phosphorylation. Conclusion: TFPI-2 over-expression may strongly inhibit the proliferation and migration of VSMCs and suppresses MMP-2, 9 activity induced by ox-LDL, making it a promising candidate for treatment of atherosclerotic process.