Increasing　evidences　suggested　macrophage　migration　inhibitory　factor　(MIF)　was　important　in　biological　activities　of　inflammatory　disease,　cancer　genesis　and　the　transition　process　from　inflammation　to　tumor.　In　our　study,　we　raised　the　missing　link　between　MIF　and　pathogenesis　of　Idiopathic　Orbital　Inflammatory　Pseudotumor　(IOIP).　IOIP　samples　were　assigned　for　bio-plex　measurement　of　41　(human　cytokines,　chemokines　and　growth　factors)　and　17　cytokines　(Th17　related　cytokines)　in　plasma　and　tissue,　respectively.　MIF　was　the　most　elevated　serological　cytokine　(IOIP　=　30060+/-4785　pg/mL;　Normal　Donor　=　1700+/-63　pg/mL).　Microarray　analysis　for　MIF　receptor　genes　in　tissue　mRNA　revealed　that　CD74　and　CXCR4　were　up-regulated　comparing　with　CD44　and　CXCR2.　Moreover,　the　expression　level　of　MIF　and　its　receptors　(CD74,　CXCR4)　were　also　confirmed　in　tissue　proteins　by　Western　Blotting　and　immunofluorescence.　We　further　found　that　the　MIF　downstream　AKT　signaling　pathway　was　activated,　targeting　at　phosphorylated-AKT,　p53,　bcl-2,　p65,　and　p50　monomers.　Analysis　of　the　Single　nucleotide　polymorphism　test　revealed　that　MIF　contributed　at　the　genetic　level,　where　MIF-173C　and　MIF-794　CATT7　alleles　were　possibly　dangerous　factors,　while　MIF-794　CATT6　allele　may　be　a　protective　factor.　This　explained　the　high　expression　degree　of　MIF　in　affective　tissue　and　plasma　at　the　gene　level.　Considering　the　massive　functions　of　MIF,　we　believe　that　during　IOIP　pathogenesis,　this　mighty　cytokine　could　be　playing　an　important　role　in　IOIP　disease　development　and　maintenance.