Lymphoproliferative disorder of natural killer cells is a heterogeneous disorder, and an association with Epstein-Barr virus (EBV) is suggested in some cases. A Japanese male presenting with recurrent nasopharyngeal problems developed fever, generalized lymphadenopathy, and hepatosplenomegaly. Separated cells from lymph nodes were shown to have a natural killer (NK) cell, CD2(Ψ), CD3(Ψ), CD16(Ψ), CD56(Ψ), HLA-DR(Ψ) phenotype. A progressive abnormality of hepatic function was associated with hepatorenal failure and death. A serologic study suggested reactivated EBV infection. In situ hybridization (ISH) studies showed Epstein-Barr virus-encoded RNA (EBER)-1 in lymph nodes, with lymphocytes infiltrating the liver and tissue from ethmoid sinus surgery 3 years prior to development of obvious lymphoproliferative disease. Polymerase chain reaction performed on lymph node DNA, using oligonucleotide primers specific for the EBV lymphocyte-determined membrane antigen (LYDMA) gene, revealed a single band, suggesting monoclonal proliferation of the tumor. NK activities of the lymphocytes from the lymph node and peripheral blood were markedly decreased. These findings suggest a close relationship between EBV infection and development of NK cell lymphoproliferative disorder.