Ubiquitin-specific protease 22 (USP22) exhibits an important function in tumor progression and oncogenesis. The aim of this study was to investigate the role of USP22 and the association with its potential targets in patients with glioma. To our knowledge, this is the first study that determines the relationship between USP22 expression and clinicopathological significance in glioma. In our study, USP22 protein levels were detected by Western blot analysis. The protein levels of USP22 in glioma tissues were significantly higher than non-tumors. The immunohistochemistry results showed that USP22 protein was overexpressed in glioma tissues compared with non-tumors. The higher the grade of gliomas, the higher the level of USP22 expression. Further, the results of Kaplan-Meier analysis indicated that patients with high USP22 expression had significantly worse overall survival than patients with low expression of USP22. It suggested that USP22 overexpression may be associated with poor prognosis in patients with glioma. It may represent a novel prognostic biomarker or a target for improving the treatment efficiency of patients with glioma.