Background and Aims The numbers of new cases and deaths of liver cancer (hepatocellular carcinoma accounts for 75%-85%) per year rank the fifth and second among those of all cancers diagnosed in China. The molecular mechanisms for HCC growth, metastasis, immune escape and treatment resistance are complex, which are the current research hotspots and difficult issues. Studies have demonstrated that the expression of tubulin ε and δ complex 2 (TEDC2) is up-regulated in a variety of malignant tumors and is associated with the prognosis. However, the clinical significance of TEDC2 in HCC has not yet been described. Therefore, this study was conducted to explore the expression of TEDC2 in HCC and its relation with the prognosis of patients.Methods The transcriptional profiles and clinicopathologic data of liver cancer were downloaded from TCGA and ICGC databases. The pan-cancer expression analysis of TEDC2 was performed through the GEPIA2 website. The relationship between TEDC2 expression and the prognosis of patients was analyzed by Kaplan-Meier method. The prognostic factors for patients were determined by univariate and multivariate Cox analyses. The biological functions associated with the expression of TEDC2 were analyzed by gene set enrichment analysis (GSEA).Results Pan-cancer analysis showed that TEDC2 was a risk factor for 6 different cancers that included ACC (adrenocortical carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LAML (acute myeloid leukemia), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma). Analyses of data from both TCGA and ICGC showed that TEDC2 expression in liver cancer tissues was significantly higher than that in normal tissues (both P<0.05). The expression of TEDC2 was related to TNM stage, T stage ang histological grade (all P<0.05), and was not associated with sex and age (both P>0.05). Survival analysis found that patients with high TEDC2 expression had shorter overall survival and disease-free survival than those with low TEDC2 expression (both P<0.05). Univariate and multivariate Cox analyses identified that TNM stage, T stage and TEDC2 expression were prognostic risk factors for HCC, but only TEDC2 expression was an independent prognostic factor in both TCGA and ICGC cohorts (all P<0.05). Results of GSEA showed that pathways related to cell proliferation were enriched in the tissues with high TEDC2 expression.Conclusion The expression of TEDC2 is increased in liver cancer tissue, and is an independent prognostic factor for liver cancer. Its high expression is closely associated with the unfavorable prognosis of patients, and the mechanism may be related to the enhanced activity of cell proliferation.