Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. E2 ubiquitin conjugating enzymes (UBE2) are potential therapeutic targets in tumors arising from genomic instability and tumor microenvironment (TME). UBE2S, an important UBE2, has demonstrated strong oncogenic activities in various malignant cancers, including HCC. However, a comprehensive study regarding its role in HCC is still absent, and its association with immunology and drug response of HCC is still unclear. In this study, we conducted a pan-cancer analysis of UBE2S expression and prognosis, carried out enrichment analysis of UBE2S-associated genes, and analyzed association between UBE2S expression and HCC microenvironment, stemness and drug response. Collectively, our results demonstrated that UBE2S expression was significantly increased in multiple types of cancer, including HCC, and harbors prognostic values for HCC. Potential function of UBE2S involves modulation of ubiquitin mediated proteolysis and cell cycle progression. Furthermore, in HCC, UBE2S expression was positively correlated with TME infiltration, microsatellite instability (MSI), DNA methylation, stemness and drug response. These findings highlighted the possible pivotal roles of UBE2S in HCC prognosis, precision immunotherapy and drug response.