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Background: The specific functions of PPP1R81 has been elucidated in multiple cancers; however, its role in lower-grade glioma (LGG) remains unknown. In this research, we inspected the specific role of PPP1R81 in LGG.  Methods: We totally evaluated the expression pattern and prognostic role of PPP1R81 in multitudinous tumors. Subsequently, we systematically examined the connection between PPP1R81 expression and prognosis, clinical characteristics, biological functions, genetic variations, and immunological characteristics in LGG according to The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Altas (CGGA) databases. In Vitro experiments were executed to inspect the expression level and specific roles of PPP1R81 in LGG.</p>  Results: PPP1R81 was elevated in multiple tumors and was tightly linked to a poor prognosis. LGG with higher expression of PPP1R81 showed poorer prognosis compared to lower expression of PPP1R81. The results of univariate and multivariate Cox regression analyses confirmed that the expression of PPP1R81 was an independent prognostic biomarker of LGG. Immune cell infiltration, immune checkpoint genes (ICPGs), copy number alterations (CNA), and tumor mutation burden (TMB) were also closely associated with PPP1R81 expression in LGG. In vitro experiments demonstrated that PPP1R81 was upregulated and closely interrelated with cell proliferation and cell cycle in LGG.</p>  Conclusion: PPP1R81 was an independent prognostic signature and underlying therapeutic target for patients with LGG.</p>