Lymphocyte-depletion Hodgkin's disease (LDHD) is a rare and often misdiagnosed form of HD. Although marrow involvement is frequent in this disease, most pathologists are not familiar with the marrow lesion of LDHD, since the underlying disease is so unusual. In order to characterize the marrow lesion produced by LDHD, we reviewed biopsies or aspirates from the initial presentation of 22 patients meeting all the clinical and pathologic criteria for LDHD. These included 11 cases of the diffuse fibrosis subtype, eight cases of reticular subtype, and three cases not subclassified. Fifty-four percent of cases, primarily of the diffuse fibrosis subtype, had marrow involvement. Aspirations and biopsies were positive with essentially the same frequency. LDHD produces a characteristic consolidated lesion readily recognized on low-power examination and composed of amorphous, nonbirefringent eosinophilic background material, an inflammatory infiltrate, and Reed-Sternberg (RS) cells. Involvement may be focal and RS cells are generally scarce, requiring examination of multiple sections of well-fixed and stained material. Uninvolved marrow tends to be normocellular and frequently has increased numbers of eosinophils. The original diagnosis of LDHD often may be made from marrow examination alone. Early recognition of marrow involvement is important in facilitating prompt treatment and providing accurate staging without laparotomy.