The GTPase-activating protein RLIP76 is overexpressed in and correlates with the pathological grade of many malignant tumor cells. But the potential correlation between RLIP76 and clinical outcomes in patients with meningioma remains unknown. In this study, we examined the expression of RLIP76 in meningioma and correlated the RLIP76 expression to the patient outcome. RLIP76 expression in tumor tissues was examined with immunohistochemistry, quantitative reverse-transcription polymerase chain reaction(RT-PCR) and Western-blot. Immunohistochemistry showed an increased RLIP76 immunostaining score in anaplastic and atypical meningiomas versus classical meningiomas. Statistical analyses revealed that RLIP76 immunostaining positively correlated with immunostaining for Ki-67, a nuclear protein highly expressed in proliferating cells(r=0.29, p=0.034 by Spearman's correlation coefficient). Clinicopathological evaluation suggested that RLIP76 expression be associated with tumor grade and recurrence(P<0.05). Univariate and Cox analysis indicated that RLIP76 was an independent prognostic factor for tumor recurrence. Furthermore, the human malignant meningioma cell lines IOMM-Lee and CH157-MN stably transfected with short hairpin RNA (siRNA) targeting RLIP76 were then examined by in vitro growth assays, and apoptosis assays. RLIP76 knockdown in IOMM-Lee and CH157-MN cells inhibited cell proliferation and induced apoptosis. Western blot analysis revealed that cells underexpressing RLIP76 exhibited decreased B-cell lymphoma-2(Bcl-2) expression but increased apoptosis effector caspase-3 expression. These findings demonstrate that high RLIP76 expression is associated with a poor outcome of meningioma and may provide a new gene therapy approach for patients with malignant meningiomas.