Programmed cell death ligand 1 (PD-L1) is cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. Previous studies have demonstrated consistent expression of PD-L1 by Reed-Sternberg (RS) cells, as well as nonmalignant tumor-infiltrating macrophages in classic Hodgkin lymphoma (CHL). Bone marrow involvement by CHL is uncommon, being present in 5% to 10% of cases, but indicates Ann Arbor stage IV disease. Given the mixed inflammatory infiltrate that characterizes CHL, detection of RS cells in small bone marrow biopsies may be difficult. We sought to investigate the diagnostic utility of PD-L1 expression in staging bone marrow biopsies from patients with newly diagnosed CHL. Forty-four staging bone marrow biopsies from patients with newly diagnosed CHL were examined for PD-L1 expression by immunohistochemistry. Eight bone marrow biopsies were positive for involvement by CHL (8/44, 18%) and all were positive for PD-L1 (8/8, 100%), including a case that was originally nondiagnostic. Membranous PD-L1 expression was restricted to RS cells and the adjacent nontumor inflammatory cells admixed within areas of fibrosis. Uninvolved bone marrow biopsies and normal-appearing marrow in cases positive for CHL were negative for PD-L1. In comparison, bone marrow biopsies with myelofibrosis caused by myeloproliferative or myelodysplastic disorders were negative for significant PD-L1 staining. PD-L1 expression in RS cells and surrounding inflammatory cells is a sensitive marker for bone marrow involvement by CHL. In cases where RS cells are infrequent, PD-L1 staining in regions of fibrosis may serve as a useful diagnostic clue to involvement by CHL.