Septins are a novel group of GTPases, which are first identified in yeast and more recently found in a wide range of animal cells. Septin-9, a novel septin family member, is expressed ubiquitously and involved in an increasing number of signaling cascades. However, information regarding its distribution and possible function in the central nervous system (CNS) is limited. In this study, western blot analysis and immunohistochemistry showed a significant upregulation of Septin-9 in the ipsilateral peritrauma cortex compared with the sham group. Immunofluorescent labeling indicated that Septin-9 was localized strikingly in the cytoplasm of neurons, but not astrocytes and oligodendrocytes. The co-localization of Septin-9 and active caspase-3 was also examined in the ipsilateral cortex. In addition, the expression patterns of active caspase-3 were parallel with that of Septin-9. Quantitative real-time RT-PCR also was used to detect Seption-9 mRNA level. Based on our data, we speculated that traumatic brain injury may be a stimulus to induce the Septin-9 expression, and Septin-9 might play an important role in the pathophysiology process in the CNS after traumatic brain injury. Taken together, this is the first description of Septin-9 expression changes during the central nervous system lesion and repair, but further studies are needed to understand the cell signaling pathway which can direct the exact role of Septin-9 following traumatic brain injury.