We report the case of a female patient with chronic active Epstein-Barr virus infection (CAEBV) accompanied by hemophagocytic syndrome (HPS). On admission, she presented with severe liver dysfunction and disseminated intravascular coagulation with elevation of serum IL-6, TNF-α, and IFN-γ levels. Plasma exchange (PE) followed by immunochemotherapy with prednisolone, cyclosporine A, and VP16 was performed. PE decreased serum cytokine levels dramatically and improved liver function. Following immunochemotherapy, CAEBV became inactive. Four months after discharge, however, CAEBV relapsed with HPS, and serum cytokine levels were extremely elevated again. There was no response to immunochemotherapy, and the patient died 1 day after admission. We examined the cytokines in five additional untreated-CAEBV patients and determined that they were elevated above the normal level in all patients. These results suggest that inflammatory cytokines may have roles in the development of CAEBV, and that their depletion can be an effective treatment for this disease.