Background: Current research suggests that the glial scar surrounding penetrating brain injuries is instrumental in preserving the surrounding uninjured tissue by limiting the inflammatory response to the injury site. We recently showed that (TNF)-stimulated gene-6 (TSG-6), a well-established anti-inflammatory molecule, is present within the glial scar. We hereby investigate the role of TSG-6 within the glial scar.Methods: TSG-6 null and littermate control mice were subjected to penetrating brain injuries, after which the injury site and remaining injured hemisphere were analyzed. The presence of activated astrocytes, inflammatory markers and glial scar components were evaluated by real-time PCR and immunohistochemistry.Results: Our findings demonstrate that mice lacking TSG-6 present a more severe inflammatory response after injury, which is correlated with an enlarged area of astrogliosis beyond the injury site.Conclusion: Our data provides evidence that TSG-6 has an anti-inflammatory role within the glial scar.