Pregnane　X　receptor　(PXR)　is　a　member　of　nuclear　receptor　superfamily　and　responsible　for　the　detoxification　of　xenobiotics.　Recent　studies　demonstrated　that　PXR　was　also　expressed　in　the　vasculature　and　protected　the　vessels　from　endogenous　and　exogenous　insults,　thus　representing　a　novel　gatekeeper　in　vascular　defense.　In　this　study,　we　examined　the　potential　function　of　PXR　in　the　neointimal　formation　following　vascular　injury.　In　the　rat　carotid　artery　after　balloon　injury,　overexpression　of　a　constitutively　active　PXR　increased　the　intima-to-media　ratio　in　the　injured　region.　PXR　increased　cell　proliferation　and　migration　in　cultured　rat　aortic　smooth　muscle　cells　(SMCs)　by　inducing　the　expressions　of　cyclins　(cyclin　A,　D1,　and　E)　and　cyclin-dependent　kinase　2.　In　addition,　PXR　increased　the　phosphorylation　and　activation　of　extracellular-signal-regulated　kinase　1/2　(ERK1/2)　and　p38　mitogen-activated　protein　kinase　(MAPK).　Inactivation　of　ERK1/2　and　p38　MAPK　pathways　using　selective　inhibitors　(U0126　and　SB203580)　abrogated　PXR-induced　SMC　proliferation　and　migration.　Furthermore,　cigarette　smoke　particles　(CSP)　activated　PXR　in　SMCs.　Knockdown　of　PXR　by　small　interfering　RNA　suppressed　the　cell　proliferation,　migration,　and　activation　of　the　MAPK　pathways　by　CSP.　These　findings　suggested　a　novel　role　for　PXR　in　promoting　SMC　proliferation　and　migration,　and　neointimal　hyperplasia.　Therefore,　PXR　may　be　a　potential　therapeutic　target　for　vascular　disease　related　to　xenobiotics　such　as　cigarette　smoking　and　other　environmental　pollutants.