This report describes lytic infection with Epstein-Barr virus (EBV) in three cases of hemophagocytic syndrome (HPS) presumably associated with EBV-induced lymphoproliferative disorder. All cases were previously healthy females with ages ranging from 52 to 87 years who showed a fulminant clinical course with accompanying fever, liver dysfunction, and disseminated intravascular coagulation. Cases 1 and 2 showed proliferation of atypical T lymphocytes, and case 3 showed proliferation of atypical B lymphocytes. Hemophagocytic histiocytes were observed in the bone marrow, lymph nodes, spleen, and liver. Atypical lymphocytes in all cases showed a positive reaction for both EBV-encoded small RNA (EBER) indicating latent infection with EBV and immediate early mRNAs of the Bam HI fragment of lower stranded frame (BHLF), indicating lytic infection by in situ hybridization. Interestingly, BHLF-positive cells were predominant in all cases. It is possible that reactivation of EBV infection may be involved in triggering the induction of cytokines and abnormal activation of histiocytes.