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Background: Tumor-infiltrating lymphocytes (TILs) constitute a prognostic factor in hepatocellular carcinoma (HCC). However, different methods of assessing TILs have various pre-analytical, analytical, and post-analytical challenges. The evaluation of TILs in hematoxylin and eosin (H&E)-stained tumor sections proposed by the International Immuno-Oncology Biomarker Working Group was demonstrated to be a reproducible, affordable and easily applied method in many tumors., Aim: To evaluate the prognostic significance of TILs in H&E-stained slides of HCCs., Methods: This was a retrospective study performed in the hospital. HCC patients who underwent liver resection between 2015 and 2017 in Zhongshan Hospital were enrolled in this study. Patients who experienced recurrence or received therapy in addition to antiviral therapy before surgery at this time were excluded. A total of 204 patients were enrolled in the study. The ILs were counted manually in tumor sections stained with H&E under an optical microscope at 400 ×. The ILs were assessed separately in the center of the tumor (TILs CT ), the invasive front (TILs IF ), and peritumor (PILs) areas. Univariate and multivariate survival analyses were performed using a Cox regression model. P < 0.05 was considered statistically significant and all P -values were two-sided., Results: Among the 204 patients, univariate analysis indicated that macrovascular invasion (MaVI) ( P = 0.001), microvascular invasion (MVI) ( P = 0.012), multiple tumors ( P = 0.008), large tumors (> 10 cm) ( P = 0.001), absence of a tumor capsule ( P = 0.026), macrotrabecular histological subtype ( P = 0.001), low density of TILs CT ( P = 0.039), TILs IF ( P = 0.014), and PILs ( P = 0.010) were predictors of progression-free survival (PFS). Cox multivariate analysis indicated that MaVI ( P = 0.009), absence of a tumor capsule ( P = 0.031), low-density of TILs IF ( P = 0.047) and PILs ( P = 0.0495) were independent predictors of PFS. A three-category analysis was carried out by combining TILs CT , TILs IF , and PILs, after which HCCs were classified into immune high [(TILs CT ) high , (TILs IF ) high , and PILs high , 83 cases], immune mod (tumors other than immune high and immune low subtypes, 94 cases), and immune low [(TILs CT ) low , (TILs IF ) low , and PILs low , 27 cases)] subtypes. The immune high subtype had a lower rate of MVI (40.96%) than the immune mod (61.70%, P = 0.017) and immune low (66.67%, P = 0.020) subtypes. The recurrence rates of the immune high , immune mod and immune low subtypes were 10.8%, 25.5% and 33.3%, respectively., Conclusion: HCC patients with high infiltrating lymphocytes tend to have a lower recurrence rate and less MVI. The evaluation of TILs in H&E-stained specimens could be a prognostic parameter for HCC., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)