Propose:　Idiopathic　orbital　inflammatory　pseudotumors　(IOIP)　are　inflammatory　pseudotumors　(IPT)　of　unknown　etiology　that　develop　in　the　orbit.　Due　to　the　lack　of　well-defined　pathogenic　mechanisms　and　diagnostic　markers,　diagnosis　and　treatment　of　this　disease　remain　a　significant　challenge.　Therefore,　the　aims　of　this　study　are　to　define　the　etiological　factors　of　IOIP　and　to　identify　potential　gene　targets　for　the　treatment　of　IOIP.　Methods:　Eleven　IOIP　tissue　samples　were　obtained　from　patients　during　surgical　resection;　as　control　tissue,　four　normal　tissue　samples　were　collected　from　surgery　removal　of　eye　due　to　trauma.　Total　RNA　was　extracted　and　the　gene　expression　profile　of　both　diseased　and　normal　tissues　was　analyzed　using　human　oligonucleotide　microarrays,　which　contained　32,050　wellcharacterized　human　genes.　The　expression　patterns　of　selected　genes　were　further　confirmed　by　Real-time　RT-PCR.　Results:　Microarray　analyses　identified　744　genes　differentially　expressed　in　IOIP　and　non-IOIP　samples,　with　at　least　2　1.5-fold　changes　and　P-value　3K　and　NF-κB　pathways,　extracellular　matrix　degradation,　and　unknown　functions.　Conclusions:　Immune　and　inflammatory　responses　and　activation　of　the　PI3K　and　NF-κB　pathways　are　likely　associated　with　IOIPs.　Drugs　that　would　suppress　these　two　responses　and　two　signal　pathways　may　offer　new　therapeutics　of　IOIP　treatment.　©　2010　IEEE.