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.