Recent　global　epidemiological　studies　revealed　the　lower　ovarian　cancer　death　from　long-term　use　of　oral　contraceptives.　However,　the　underlying　mechanism　of　action　is　not　clear.　Here,　we　use　the　abortifacient　metapristone　(RU486　derivative)　to　test　the　hypothesis　that　the　contraceptives　might　interrupt　CXCL12/CXCR4　chemokine　axis　to　inhibit　ovarian　cancer　metastasis.　Metapristone　at　concentrations　(＜IC50)　remarkably　reduces　CXCL12-induced　CXCR4　expression　on　ovarian　SKOV-3　and　IGROV-1　cell　lines,　and　down-regulates　the　CXCR4-related　mRNAs　and　intracellular　proteins.　Metapristone　concentration-dependently　inhibits　cancer　cell　proliferation　via　interfering　the　CXCL12-activated　Akt　and　ERK　signaling　pathways.　The　effect　of　CXCL12　could　be　antagonized　by　AMD3100.　Metapristone　interrupts　the　cellular　filamentous　actin　polymerization　and　the　related　chemotaxis.　Metapristone　also　concentration-dependently　inhibits　the　events　of　cellular　invasion,　migration,　and　adhesion.　The　inhibition　is　related　to　down-regulation　of　the　invasive　molecules　MMP-2,　MMP-9,　COX-2,　and　VEGF　without　affecting　the　adhesion　molecules　ICAM-1,　integrins　1,　3,　5,　6,　and　1.　Six-week　in　vivo　xenograft　study　confirms　the　anti-metastatic　effect　of　metapristone　on　mouse　ascites　and　metastatic　foci　induced　by　intraperitoneal　IGROV-1　and　CXCL12.　The　present　studies,　for　the　first　time,　reveal　the　therapeutic　effect　of　metapristone　on　ovarian　metastasis　and　the　CXCL12/CXCR4　axis-related　mechanisms　of　actions.