Epstein-Barr virus (EBV)-associated lymphoproliferative diseases are a frequent occurrence in immunodeficient patients. Most commonly seen are polymorphic B-cell lymphoproliferative disorders and malignant B-cell lymphomas. Classical Hodgkin's disease (HD), however, is rare in these patients. In the present study, we attempted to characterize cases resembling HD in patients with a variety of underlying immunodeficiency states using clinical aspects, immunohistochemistry, in situ hybridization, and polymerase chain reaction. All of the six cases that we investigated presented clinically with B symptoms and a short, devastating course. Histologically, they showed a lymphocytic depletion and multiple cells that resembled HD and Reed-Sternberg cells. Many of those were atypical blast cells that stained positively for B-cell surface antigens, such as CD20 and CD79a, whereas others were of the typical HD and Reed-Sternberg phenotype. Another frequent finding, especially in the extranodal sites, was a perivascular arrangement of large blast cells intermingled with small lymphoid cells. All of the cases were EBV-associated (proved latent membrane protein-1 immunohistochemical analysis, EBV-encoded RNA in situ hybridization, and polymerase chain reaction for subtypes A and B), with a frequent coinfection of type A and B. This was in contrast to ordinary HD, which is characterized by single infection of only one strain, i.e., the subtype A in Western countries. Three cases showed clonal B-cell populations, at least at terminal stages of the disease. We describe a lymphoproliferative disorder in immunodeficient patients with features of HD that, in some respects, resembles an EBV-driven lymphoproliferative disorder seen in cases of fatal infectious mononucleosis. We conclude that clinical and pathologic features of these disorders might cause some problems for histologic differential diagnosis and might represent a separate entity of their own in immunodeficient patients.