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Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non–Hodgkin lymphoma, usually presents in older adults with slightly increased incidence in males. Untreated, it has an aggressive course, but a remarkable increase in cure rates has resulted from combination chemoimmunotherapy, combining rituximab with chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone. With chemoimmunotherapy, increasing dose intensity or administration of more than 6 cycles does not seem to improve results significantly. The International Prognostic Index remains prognostic, and although gene expression profiling can identify subgroups with differing prognoses, they have yet to determine treatment choices in clinical practice. In human immunodeficiency virus–associated DLBCL, rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seems to improve event-free and overall survival. More than 30% of DLBCL cases will ultimately relapse, requiring high-dose therapy with autologous stem cell transplantation. Newer agents targeting specific molecular pathways involved in pathogenesis are being studied in the maintenance and relapsed settings.