AbstractBackground & AimsLymphocyte‐rich hepatocellular carcinoma (LR‐HCC) is largely unknown and a rare subtype of HCC with immune‐rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR‐HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated.MethodsClinicopathologic data of 191 cases of surgically resected conventional HCC (C‐HCC, n = 160) and LR‐HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated.ResultsLR‐HCC was significantly correlated to larger tumour size, higher Edmondson–Steiner grade, presence of TLS and higher CD3‐, CD8‐ and FOXP3‐positive T cell, high PD‐1 and PD‐L1 expression (p < .001 for all) compared to C‐HCC. Patients with LR‐HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence‐free survival (RFS) (p = .025) than C‐HCC. LR‐HCC demonstrated TLS signatures with significantly higher proteomic‐based immune scores in 14 of 17 types of tumour‐infiltrating immune cells. Furthermore, C‐HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR‐HCC was well‐differentiated from C‐HCC and a map of protein–protein interactions between tumour‐infiltrating lymphocytes and HCC in tumour microenvironment was completed.ConclusionLR‐HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C‐HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR‐HCC and C‐HCC.