Background: Thioredoxin domain containing 11 (TXNDC11) has been implicated in numerous cancers. Nevertheless, the function of TXNDC11 in glioma is not well described. This study aimed to assess clinical significance of TXNDC11 in glioma based on bioinformatics analysis and immunohistochemical (IHC) staining. Methods: GEPIA2, The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases were employed to detect the levels of TXNDC11 transcript in glioma. Gene expression profiles and data from the methylation chip with clinical details from TCGA and Chinese Glioma Genome Atlas (CGGA) of glioma samples were examined. The methylation of TXNDC11 in glioma was evaluated by 450K methylation chip data analysis. The pathways involved in TXNDC11 expression were screened by gene set enrichment analysis ( GSEA). The correlation between TXNDC11 and immune cells was analyzed. Protein level of TXNDC11 was detected by IHC staining in glioma specimens. Results: TXNDC11 was highly expressed in glioma, and high TXNDC11 expression was associated with poor overall survival (OS) and worse clinical prognostic variables. The methylation of cg04399632 was statistically different between glioma samples and normal samples, and was negatively correlated with TXNDC11 expression in glioma patients. Survival analysis demonstrated a poorer prognosis in glioma patients with cg04399632 hypomethylation. TXNDC11-high phenotype was associated with certain immune-related pathways and other signaling pathways in glioma. The expression of TXNDC11 was correlated positively with M2 macrophage infiltration and negatively with M0 and M1 macrophage infiltration. IHC staining confirmed that TXNDC11 expression increased in higher-grade glioma. Conclusions: High expression of TXNDC11 may predict unfavorable prognosis of glioma patients.