AbstractMulticentric Castleman's disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type‐1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposi's sarcoma‐associated herpesvirus proteins, and most HIV‐associated MCD features can be attributed to the presence of this γ‐herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon‐α, foscarnet, ganciclovir, and antibodies to interleukin‐6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti‐CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposi's sarcoma. MCD represents a model of disease at the interplay between tumor biology, infection, and immunology. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.