We report a case of aggressive natural killer cell lymphoma presenting as an anterior mediastinal mass in an African-American man with acquired immunodeficiency syndrome. Histologically, the anterior mediastinal mass showed a diffuse dense infiltrate of atypical intermediate-sized and large lymphoid cells, as well as scattered immunoblasts with angiocentric and angiodestructive growth and extensive zonal necrosis. Similar lymphoid infiltrates were present in the patient's lungs, spleen, and bone marrow, accompanied by extensive lymphophagocytosis. Electron microscopic and cytologic examinations showed the presence of dense cytoplasmic granules. Immunophenotyping by flow cytometry and by immunohistochemistry yielded surface markers consistent with a natural killer cell lymphoma. The Epstein-Barr virus genome and monoclonality were detected by in situ hybridization and Southern blot analysis. Polymerase chain reaction confirmed the presence of type A Epstein-Barr virus. T-cell receptor gene rearrangement could not be identified by Southern blot analysis or polymerase chain reaction. To the best of our knowledge, this is the first reported case of designated natural killer cell lymphoma from the mediastinum, as well as the first reported case of natural killer cell lymphoma in a patient with acquired immunodeficiency syndrome. This tumor disseminated early and pursued a highly aggressive course. Epstein-Barr virus may play a role in the pathogenesis of this disease.