Epstein-Barr virus (EBV) infection is associated with various lymphoproliferative diseases, including Hodgkin lymphoma, extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma and post-transplant lymphoproliferative disorder. In the recent studies, the plasma EBV-DNA levels in patients with EBV-associated lymphoproliferative disease appeared to be correlated with the therapeutic response. Aggressive NK cell leukemia (ANKL) is a fatal disease that's characterized by high fever, lymphadenopathy, hepatosplenomegaly and frequent hemophagocytosis. No serological tumor marker for this malignancy has yet been identified for monitoring the disease and predicting the outcome. We experienced a case of aggressive natural killer cell leukemia in a 48-year-old man, and we serially monitored the plasma EBV DNA load by performing real time quantitative PCR assay. Serial measurements of the plasma EBV DNA level during therapy showed a close correlation between the clinical response and the changes in the plasma EBV DNA titers.