A detailed clinicopathologic analysis of 52 cases of fatal infectious mononucleosis was performed. Fever, rash, generalized lymphadenopathy, hepatosplenomegaly, and blood cytopenias were the characteristic findings. Epstein-Barr virus infection was documented in 44 of the 52 patients. A triphasic process evolved in the blood and bone marrow of 43 patients. Early, the leukocyte count was elevated due to numerous atypical lymphoid cells, and the marrow was hyperplastic. Later, severe pancytopenia developed, and the marrow showed extensive infiltration by lymphoid cells with cellular necrosis and histiocytic hemophagocytosis. Terminally, the marrow showed massive necrosis with severe cellular depletion and marked histiocytic hemophagocytosis. The median survival time of the patients was six weeks. Opportunistic infections and/or acute hemorrhage were the major causes of death. We conclude that bone marrow damage secondary to an Epstein-Barr virus-associated hemophagocytic syndrome plays a major role in the death of patients with infectious mononucleosis.