Background: CBX3 is a key gene that is involved in immune cell regulation, however, its prognostic values and its correlation with infiltrating lymphocytes in various cancers have not been clearly established. This study aims to investigate the role CBX3 in hepatocellular carcinoma (HCC).Methods: We first reviewed the expression of CBX3 in different cancers and adjacent tissues using oncomine database. Next, the authors focus on the expression of CBX3 in hepatocellular carcinoma. Therefore, the expression of CBX3 in hepatocellular carcinoma were analyzed through UALCAN online analysis website and the Human Protein Atlas (www.proteinatlas.org) website. In addition, we further found that CBX3 can be identified as an effective marker for the prognostic guidance of hepatocellular carcinoma according to the Kaplan-Meier plotter database and the Bioinformatics analysis online websites (www.aclbi.com). Next, we used the Bioinformatics analysis online websites to explore whether the expression level of CBX3 in liver cancer is related to the infiltration of certain immune cells. In addition, we also predicted the correlation between immune checkpoint and CBX3 in liver cancer.Results: The analysis results preliminarily show that CBX3 be expressed abnormally in many cancers, and CBX3 was significantly up-regulated in HCC. The high expression of CBX3 indicated survival outcomes and it showed a huge potential as a effective marker for the prognostic guidance of hepatocellular carcinoma. Furthermore, we found that CBX3 in liver cancer is related to the infiltration of certain immune cells, including CD4+ T cells, macrophages and B cells. In addition, the results showed HAVCR2 is most likely to become an effective immune checkpoint for HCC patients immunotherapy with high CBX3 expression.Conclusions: CBX3 is a potential diagnostic and prognostic marker in HCC and related to the infiltration of certain immune cells. It is expected to become a breakthrough point in immunotherapy in the future.