BACKGROUND: Glycolysis is a crucial metabolic pathway for energy production in tumor cells. This study aimed to identify glycolysis-related genes (GRGs) that are linked to the prognosis of oral squamous cell carcinoma (OSCC) and to develop a prognostic model based on these GRGs. METHODS: Transcriptomic data were obtained from The Cancer Genome Atlas (TCGA) database. A gene set enrichment analysis (GSEA), univariate and multivariate Cox proportional hazards analyses, and a least absolute shrinkage and selection operator (LASSO) regression analysis were used to identify the prognostically relevant GRGs, and construct a predictive model and risk-score system. A nomogram integrating the gene-based risk signature and clinical variables was subsequently established. The predictive performance of the model was validated using an external dataset obtained from the Gene Expression Omnibus (GEO) platform. Additionally, the association of the risk score with immune cell infiltration levels was assessed through CIBERSORT and TIMER, tools specifically designed for deconvoluting and quantifying immune cell populations from bulk gene expression data. RESULTS: The risk score was established based on six GRGs (i.e., , , , , and ), which were independent risk factors in the prognosis of OSCC according to multivariate Cox regression analysis [hazard ratio (HR): 1.208, 95% confidence interval (CI): 1.116-1.308, P<0.001]. Taking the median value of the risk score as the cut-off value, the patients were allocated to high- and low-risk cohorts. The Kaplan-Meier (KM) survival curve showed that the patients in the low-risk group had significantly improved overall survival. The six GRGs were then included in a nomogram, which showed excellent predictive capability in both TCGA and GEO datasets. The patient's risk score was associated with the infiltration levels of specific immune cells, including regulatory T cells, resting mast cells, and activated mast cells. This study was conducted based on comprehensive bioinformatics analysis of GRGs. CONCLUSIONS: The GRG-based risk score and prognostic nomogram could serve as tools for predicting clinical outcomes in OSCC patients. Moreover, enhanced glycolytic activity is associated with immune cell infiltration in the tumor microenvironment, suggesting a promising avenue for the development of immunotherapeutic strategies and novel anti-cancer targets in OSCC.