Virus-associated hemophagocytic syndrome (VAHS) has been thought to be a distinct clinical entity, characterized by intermittent fever, enlarged liver and spleen, and the appearance of hemophagocytosis. Hemopoietic cells are actively ingested by monocytes/macrophages in various organs, including lymph nodes, bone marrow, liver, and spleen. Epstein-Barr virus (EBV) is now thought to be one of the major causes for the development of this unique syndrome. Additionally, VAHS is often associated with fatal infectious mononucleosis (IM). The relationship between EBV-associated VAHS and fatal IM is discussed in this concise review.