Background and Aims The gene solute carrier family 2 member 1 (SLC2A1) encodes the glucose transporter 1 (GLUT1), which is closely related to the glycolysis pathway. Glycolysis is a primary physiological pathway for energy supply in malignant tumors. Therefore, SLC2A1 may be involved in the occurrence and development of various malignant tumors. Given that the expression and biological function of SLC2A1 in hepatocellular carcinoma (HCC) are not fully understood, this study was conducted to investigate the expression and significance of SLC2A1 in HCC through bioinformatics methods and clinical research.Methods The RNA-seq data and clinical information of HCC patients were downloaded from the TCGA database. The expression of SLC2A1 in HCC, its prognostic value, and the differentially expressed genes in HCC patients with different levels of SLC2A1 expression were analyzed through enrichment and correlation analysis. Surgical specimens and clinicopathologic data from 80 HCC patients treated at Northern Jiangsu People's Hospital were collected. The expression of SLC2A1 in HCC and its relationship with clinicopathologic characteristics and prognosis were analyzed. Independent risk factors affecting the prognosis of patients were also screened.Results The analysis of the TCGA database showed that SLC2A1 mRNA was highly expressed in HCC. Patients with high expression had significantly worse overall survival (HR=2.50, 95% CI=1.76-3.56, P<0.001), disease-specific survival (HR=2.13, 95% CI=1.34-3.37, P=0.001), and recurrence-free survival (HR=1.42, 95% CI=1.05-1.93, P=0.025) compared to those with low expression. The expression level of SLC2A1 was closely related to RNA methylation and the degree of immune cell infiltration (all P<0.05). Comparative analysis of clinical pathological data from 80 patients showed that the expression of SLC2A1 protein in HCC tissues was significantly higher than in adjacent non-tumor tissues (P<0.05). SLC2A1 expression level was significantly associated with TNM stage, hepatitis B infection, and vascular invasion (all P<0.05). Univariate analysis showed that TNM stage (HR=1.921, 95% CI=1.365-1.554, P=0.01), vascular invasion (HR=1.925, 95% CI=1.253-2.958, P=0.003), hepatitis B infection (HR=1.365, 95% CI=0.624-1.654, P=0.029), alpha-fetoprotein (HR=1.629, 95% CI=1.063-2.479, P=0.025), and SLC2A1 (HR=1.934, 95% CI=1.261-2.965, P=0.002) were associated with patient prognosis. Multivariate analysis indicated that vascular invasion (HR=1.657, 95% CI=1.036-2.652, P=0.035) and SLC2A1 (HR=1.753, 95% CI=1.132-2.715, P=0.012) were independent risk factors for the prognosis of HCC patients.Conclusion SLC2A1 is highly expressed in HCC, and its high expression is closely related to poor prognosis in patients. Besides its role in glycolysis, SLC2A1 may have various biological functions. Further research on SLC2A1 may potentially identify new targets for the prevention, treatment, and prognostic evaluation of HCC.