Using structure based genome mining, we identified a novel single transmembrane protein with two Ig domains. In this work, we show that the protein, GlialCAM, is predominantly expressed in glial cells in mouse and human nervous system, specifically in white matter tracts and ependymal lining of the CNS. GlialCAM plays a potential role in myelination. In vitro, GlialCAM is expressed in various developmental stages of oligodendrocytes and astrocytes. Moreover, sGlialCAM enhances oligodendrocyte precursor cell (OPC) migration, presumably due to reduced GlialCAM mediated contact between OPCs. Accordingly, GlialCAM deficient OPCs show enhanced migration compared to wiltype controls. Furthermore, GlialCAM is downregulated in oligodendrogliomas and astrocytomas, most likely through DNA hypermethylation. Finally, preadministration of sGlialCAM, through interactions with mannose binding lectin C (MBL-C) and properdin reduces the TNFα cytokine response after LPS stimulation in mice. Overall, the data presented here demonstrate diverse functions of GlialCAM in glial cell biology.