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Hemophagocytic lymphohistiocytosis is a rare, life-threatening complication of Epstein Barr virus (EBV) infection. Current treatments are directed at reducing virus-induced immune dysregulation. Addition of agents that eliminate EBV-infected B cells may improve therapeutic efficacy. On the basis of the observations that the anti–CD-20 monoclonal antibody rituximab reduces disease burden in individuals with EBV-associated lymphoproliferative disorders, we treated a patient with severe EBV-hemophagocytic lymphohistiocytosis using a combination of rituximab and chemotherapy. This patient demonstrated a rapid clinical response and an 18-fold reduction in EBV viral load within 24 hours of receiving rituximab. He remains free of disease 8 months after completing treatment.