We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice. Display omitted •Proteomic subgroups stratify patient survival and allocate specific treatments•Alterations of the liver-specific proteome and metabolism in HCC are identified•Multi-omics profile of key signaling and metabolic pathways in HCC is depicted•CTNNB1 mutation-associated ALDOA phosphorylation promotes HCC cell proliferation Proteogenomic characterization of HBV-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues identifies three subgroups with distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics.