Liver hepatocellular carcinoma (LIHC) is the most prevalent liver malignancy, often diagnosed at advanced stages, and resulting in a poor prognosis for patients. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific processing proteases (USPs) subfamily and has been identified as a gene signature associated with various cancer types in previous studies. However, the exact role of USP22 in LIHC remains to be fully elucidated.Multiple online bioinformatics databases were usedto investigate gene expression patterns, prognosis, mutations, and immune infiltration in LIHC patients. The UALCAN database was employed to analyze the gene expression of USP22 and its correlation with clinicopathologic data. The cBioPortal database was used to analyze the mutation status, and the Human Protein Atlas (HPA) database was utilized to illustrate the protein's localization. The STRING and GeneMANIA databases were employed to establish the protein-protein interaction (PPI) network. The GEPIA2 database was used to identify the top 100 genes correlated with USP22 in LIHC, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the 'clusterProfiler' R package. The TISIDB database was used to analyze the correlation between the USP22 gene and immune infiltration in LIHC.USP22 was upregulated in LIHC, with high levels of USP22 correlating with poor overall survival (OS) (P=0.019) and showing associations with tumor stage, histologic subtype, and TP53 mutant status. Immunohistochemistry data showed that USP22 localized in the nucleus of hepatocytes. Nine proteins, including ATXN7, ENY2, TRRAP, TAF5L, TADA3, TADA1, SUPT3H, SUPT20H, and ATXN7L3, were identified as the hub binding proteins in PPI networks. GO and KEGG enrichment analyses indicated that the genes correlated with USP22 in HCC were involved in histone modification, RNA splicing, and regulation of mRNA metabolic processes and were associated with the Notch signaling pathway, ubiquitin-mediated proteolysis, and the Wnt signaling pathway. Moreover, USP22 expression exhibited a significant negative correlation with immune infiltration by CD8+ T cells, macrophages, monocytes, and NK cells.The prognostic relevance of USP22 in LIHC was found by leveraging data from multiple databases, providing fresh insight that targeting USP22 may help develop new therapeutic approaches for LIHC.