OBJECTIVES: Gliomas, primary tumors of the central nervous system, and periodontitis, a chronic inflammatory disease impacting oral health, have both been subjects of extensive research due to their significant impact on patients' well-being. This study delves into the question of whether there is a causal relationship between glioma and periodontitis, mediated by systemic immunological changes. METHODS: This research draws from a wealth of publicly available genetic data, including genome-wide association studies for glioma, periodontitis, and immune cell traits. A comprehensive Mendelian randomization (MR) analysis is conducted, incorporating multiple MR methods and statistical tests to assess causality and account for possible biases. RESULTS: The findings indicate that individuals genetically predisposed to glioma face an increased risk of developing periodontitis. Furthermore, CD8 upregulation on NKT cells was identified as a mediator in this causal pathway, providing a partial explanation for the observed connection. This discovery aligns with clinical observations of glioma patients exhibiting a higher prevalence of poor periodontal health. CONCLUSIONS: This study advances our understanding of the complex interplay between glioma and systemic diseases like periodontitis. It underscores feasible implications for patient care and opens avenues for future research to explore the mechanistic underpinnings of this relationship.