Reactive astrocytes respond to central nervous system (CNS) injury and disease by elaborating a glial scar that is inhibitory to axonal regeneration. To identify genes that may be involved in the astrocytic response to injury, we used differential display polymerase chain reaction and an in vivo model of the CNS glial scar. Expression of the trabecular meshwork inducible glucocorticoid response (TIGR) gene was increased in gliotic tissue compared with the uninjured cerebral cortex. Increased TIGR expression by reactive astrocytes was confirmed by in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and immunohistochemistry. Although mutations of the TIGR gene have been implicated in glaucoma, a function for TIGR has not been reported. Since TIGR is secreted, we assessed a possible role in inhibition of neuronal regeneration with an in vitro bioassay and found that this protein is a potent inhibitor of neurite outgrowth. Thus, TIGR is a newly identified component of the CNS glial scar that is likely to contribute to neuronal regenerative failure characteristic of the mammalian CNS.