OBJECTIVE To describe lymphoma associated with human immunodeficiency virus (HIV) infection. METHODS A review of HIV-related lymphoma and its associated epidemiology, etiopathogenesis, and clinicopathologic characteristics is presented. Major studies of therapeutic regimens for HIV-related lymphoma are discussed. Factors that could contribute to a poor prognosis are summarized. RESULTS Malignant lymphoma that develops in patients with HIV infection fulfills diagnostic criteria for the acquired immunodeficiency syndrome (AIDS). The incidence is increasing and varies by subtype of lymphoma, age, sex, race, and risk factors. B-cell hyperactivation is thought to contribute to the development of lymphoma. The mechanisms that may show transformed cell hyperproliferation and clonal expansion are HIV itself or other viruses (for example, Epstein-Barr virus), growth factors, aberrant oncogene or tumor-suppressor gene expression, and factors that induce genetic instability or DNA damage or alter host or viral genome repair. Treatment of HIV-related lymphoma is associated with toxicity, infectious complications, low rate of complete response, and brief median survival time. CONCLUSIONS Persons with HIV-induced immune dysregulation have a high risk for the development of aggressive non-Hodgkin's lymphoma characterized by histologic evidence of a high-grade malignant process, B-cell phenotype, an unusual extranodal involvement, and a poor prognosis. The potential role of specific viruses, antiviral treatments, and other therapeutic strategies are future areas of investigation.