Objective To investigate the application value of the human B cell-confinement receptor P2RY8 in the diagnosis and prognosis of hepatocellular carcinoma (HCC) and its association with tumor immunity. Methods The Cancer Genome Atlas database was used to compare the expression of P2RY8. R software package was used to analyze the correlation between P2RY8 and tumor staging, and the receiver operating characteristic (ROC) curve and a nomogram model were established for diagnosis and survival. Tumor Immune Evaluation Resource was used to analyze immune cell infiltration, immune cell biomarkers, and immune checkpoints. STRING database was used to analyze protein-protein interaction network information. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to analyze the function of P2RY8 and its interacting genes. For the purpose of validation, HCC tissue samples were collected from 64 patients who underwent radical surgery for HCC from June 2007 to November 2008, and the corresponding adjacent tissue samples were collected from 35 patients out of these patients (tissue chips were purchased from Shanghai Outdo Biotech Co., Ltd.); related clinical data and follow-up data were analyzed, and immunohistochemistry was used to measure the expression of P2RY8 in HCC and adjacent tissue samples. The t -test was used for comparison of normally distributed continuous data between two groups; the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups. The chi-square test was used for comparison of categorical data between two groups. A Spearman correlation analysis was used to investigate the correlation between two variables. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used to calculate survival rates. Results P2RY8 was overexpressed in HCC, and the expression level of P2RY8 could accurately differentiate tumor from normal tissue, with an area under the ROC curve of 0.794. The patients with a higher expression level of P2RY8 tended to have a better prognosis ( P =0.005). The data from 64 clinical samples also confirmed that compared with the patients with a low expression level of P2RY8, the patients with a high expression level of P2RY8 had significantly higher 3-year survival rate (78.9% vs 46.2%, P =0.007), 5-year survival rate (76.3% vs 38.5%, P =0.002), and overall survival time [92.5 (48.8-102.0) months vs 33.0 (25.0-95.5) months, P =0.022], and the Kaplan-Meier survival curve further indicated that the expression level of P2RY8 was associated with the prognosis of HCC patients. In addition, P2RY8 was positively correlated with immune cell infiltration and immune checkpoint in HCC. The GO/KEGG pathway enrichment analyses showed that P2RY8 was enriched in the signal transduction pathways such as humoral immunity and cellular immunity. Conclusion P2RY8 participates in the development, progression, and immune regulation of HCC, and therefore, P2RY8 can serves as a potential biomarker and a therapeutic target for the diagnosis and prognosis of HCC.