The leucine-rich, glioma-inactivated (LGI1) gene, located in 10q24, was originally identified because it was interrupted and inactivated by a reciprocal chromosome translocation in the T98G glioma cell line. Loss of LGI1 expression in high-grade brain tumors is correlated with the frequent loss of chromosome 10 during progression of gliomas. To investigate whether this gene can suppress the malignant phenotype in glioma cells, we introduced the LGI1 gene into cells that do (U87) and do not (T98G and A172) express LGI1 endogenously. A172 and T98G cells showed a significant reduction in cell proliferation potential as a result of re-expression of LGI1, whereas U87 cells did not. Using BD matrigel matrix chamber assays we were also able to show that the migration ability of the reconstituted A172 and T98G cells was also reduced considerably. Finally, these reconstituted T98G and A172 cells showed a significant reduction in the ability to form colonies in soft agar compared with the parental cells. This analysis clearly demonstrates that re-expression of the LGI1 gene in glioma cells that were null for its activity can greatly reduce their malignant potential. These observations provide the opportunity to investigate the role of LGI1 in gliomagenesis and, since LGI1 is predicted to be a membrane-bound protein, potentially provides the opportunity to develop novel treatment strategies for malignant gliomas.