Hepatocellular carcinoma (HCC) is a heterogeneous disease that occurs in the setting of chronic liver diseases. The role of glycosyltransferase (GT) genes has recently been the focus of research associated with tumor development. However, the prognostic value of GT genes in HCC remains unclear. Therefore, this study aimed to identify GT genes related to HCC prognosis through bioinformatics analysis. We firstly constructed a prognostic signature based on four GT genes using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses in The Cancer Genome Atlas (TCGA) dataset. Next, the risk score of each patient was calculated, and HCC patients were divided into high- and low-risk groups. Kaplan-Meier analysis showed that the survival rate of high-risk patients was significantly lower than that of low-risk patients. Receiver operating characteristic (ROC) curves assessed that risk scores calculated with a four-gene signature could predict 3- and 5-year overall survival (OS) of HCC patients, revealing the prognostic ability of this gene signature. Moreover, univariate and multivariate Cox regression analyses demonstrated that the risk score was an independent prognostic factor of HCC. Finally, functional analysis revealed that immune-related pathways were enriched and the immune status was different between the two risk groups in HCC. In summary, the novel GT gene signature could be used for prognostic prediction of HCC. Thus, targeting the GT genes may serve as an alternative treatment strategy for HCC.Copyright © 2022 Qiang Cai et al.