The nuclear autoantigen SP100 (speckled protein 100) is reported to control cellular gene expression, cell growth and differentiation. To investigate its relevance in brain tumors, we investigated SP100 expression and function in human glioblastomas and meningiomas. SP100 was expressed in both tumors at the mRNA and protein levels in situ and in vitro, however, expression in meningioma samples and meningioma cells exceeded that in glioblastoma samples and cultivated cells significantly. Moreover, whereas nearly all meningioma cells were SP100-immunopositive, only part of the glioblastoma cells were SP100 stainable. In vitro, SP100 was upregulated by interferon-α and -γ in both malignant cell types. To study its functional role, SP100 was overexpressed in glioblastoma cells. This SP100 overexpression reduced considerably the glioblastoma cell proliferation and migration to fetal calf serum. We conclude that SP100 expression reduces malignancy of brain tumors. Since meningiomas show a generally higher SP100 expression, this may be one of the factors explaining their lower malignancy compared to glioblastomas.