BACKGROUND: Glioma, a highly aggressive brain tumor, presents significant challenges in prognosis and treatment. This study investigates the role of PTX3 expression in glioma and its correlation with patient outcomes, addressing a gap in current research regarding its molecular mechanisms. MATERIALS AND METHODS: RNA sequencing data and clinical information for glioma patients were obtained from The Cancer Genome Atlas (TCGA). A multigene prognostic signature based on IL-18 signaling-related genes (ISRGs) was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression method. The functional roles of PTX3 were analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Single-sample GSEA (ssGSEA) was used to assess the association between PTX3 expression and immune cell infiltration. The relationship between PTX3 expression and clinicopathological features was also examined. Prognostic relevance was evaluated using univariate and multivariate Cox regression models, and Kaplan-Meier survival analysis was performed. PTX3 protein expression was validated via immunohistochemistry in 56 glioma specimens. RESULTS: The LASSO Cox regression model identified a nine-gene prognostic signature, including BMP2, NCF1, HSPB1, PIGT, PTX3, CCNA2, CCNB2, CCN4, and DES. Functional enrichment analysis revealed that PTX3-associated differentially expressed genes were significantly enriched in pathways such as cytokine-cytokine receptor interaction and PI3K-Akt signaling, which are critical for immune response and cell proliferation in glioma. PTX3 expression showed a strong correlation with immune cell infiltration, particularly macrophages, neutrophils, T cells, and natural killer cells, suggesting a role in modulating the tumor microenvironment. Pan-cancer analysis indicated that PTX3 is markedly upregulated in various cancers, especially gliomas, highlighting its potential as a biomarker. PTX3 expression was also associated with clinical features such as WHO grade, IDH mutation status, and 1p/19q co-deletion, with higher PTX3 levels linked to poorer survival outcomes. Immunohistochemistry confirmed elevated PTX3 protein expression in both lower-grade glioma and glioblastoma multiforme. CONCLUSIONS: These findings highlight the critical role of PTX3 in glioma and suggest its potential as both a prognostic biomarker and therapeutic target. This study provides a foundation for future research into targeted therapies involving PTX3.