Description: Aims Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis. Human leukocyte antigen (HLA) and β2M serve as key molecules in tumor immunity, and their expression is frequently reduced in tumor cells. Programmed cell death (PD)-1/PD-ligand1 (PD-L1) interactions play a role in escape of tumor cells from T-cell immunity. Therefore, this study aimed to determine the clinicopathological relevance of HLA and β2M expressions in ATLL cells and PD-L1 expression in lymphoma or stromal cells and predict the overall survival of patients with ATLL. Methods & Results We analyzed a total of 123 biopsy samples from patients newly diagnosed with ATLL by using immunohistochemical analysis. Of the patients enrolled, 91 (74%) were positive for HLA (in cell membrane, 60 patients), 89 (72%) were positive for β2M (in cell membrane, 54 patients), and 48 (39%) were positive for both HLA and β2M in the cell membrane (HLA m+ β2M m+ ). No significant clinical differences other than prognosis were found between the HLA m+ β2M m+ group and the other groups. Immunophenotypical evaluation revealed significantly higher rates of CD30-positive lymphoma cells ( P = 0.003) and PD-L1–positive stromal cells in microenvironments (miPD-L1 high ) ( P = 0.011) of the HLA m+ β2M m+ group than in the other groups. The HLA m+ β2M m+ group had significantly better prognosis that the other groups ( P = 0.0096), and patients showing HLA m+ β2M m+ with miPD-L1 high had the most-favorable prognosis among all groups. Conclusions The membranous expression of HLA and β2M is likely to reflect the immune response and would be useful to predict prognosis before starting ATLL therapy. This article is protected by copyright. All rights reserved.