Stomatin-like protein 2 (STOML2), a member of the stomatin family, has been reported to be up-regulated in several types of human cancers. The clinical significance and biological role of STOML2 in gliomas remain largely unknown. Here, we describe the significantly up-regulated expression of STOML2 in glioma cell lines and glioma tissues at both the transcriptional and translational levels. Silencing endogenous STOML2 in glioma cells and primary glioma cells drastically reduced their migratory speed and invasive ability, associated with induction of matrix metallopeptidase 9 (MMP-9). We also demonstrated that knockdown of STOML2 significantly inhibited the transcriptional activity of NF-κB and repressed the expression levels of NF-κB target genes, including MMP-9. A luciferase reporter assay revealed that the impact of STOML2 on MMP-9 expression is NF-κB-dependent. Immunohistochemical analysis showed that the up-regulation of STOML2 was significantly correlated with the WHO histological grade of gliomas (p < 0.001). Patients with higher STOML2 expression levels had an overall shorter survival time, whereas patients with lower expression of STOML2 had a longer survival time. A multivariate analysis revealed that STOML2 expression might be an independent prognostic indicator for the survival of glioma patients. Taken together, our results suggest that overexpression of STOML2 is associated with glioma aggressiveness and may represent an independent prognostic factor for the outcome of glioma patients. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.