Natural killer cell leukemia (NK leukemia) is an aggressive form of lymphoproliferative disease of granular lymphocytes, and frequently complicates fulminant hemophagocytic lymphohistiocytosis. NK leukemia cells usually possess a single episomal form of Epstein-Barr virus (EBV), and therefore originate from a single EBV-infected NK cell. The NK leukemia cells lack endogenous Bcl-2 expression and are sensitive to apoptotic cell death. However, they constitutively produce interferon-gamma and maintain their survival in an autocrine fashion. The interferon-gamma released from NK leukemia cells may trigger the occurrence of hemophagocytic lymphohistiocytosis through activating macrophages/histiocytes. In the primary infection of EBV, T cells infected with the episomal form of EBV sometimes produce a high amount of interferon-gamma that may lead to the occurrence of hemophagocytic lymphohistiocytosis. Thus, it is important to determine the role of EBV in the increased production of interferon-gamma that occurs in EBV-infected T and NK cells to clarify the developmental mechanism of NK leukemia and its paraneoplastic hemophagocytic lymphohistiocytosis.