The virus-associated hemophagocytic syndrome (VAHS) is a disorder characterized by a benign, generalized histiocytic proliferation, with marked hemophagocytosis associated with systemic viral infections. We have studied the virological and immunopathological events occurring in two children experiencing Epstein-Barr VAHS. Neither of the patients had an underlying immunodeficiency and both recovered from their disease and are completely well one year after follow-up. In each patient, evidence for primary Epstein-Barr virus (EBV) infection was documented with a typical humoral immune response, including IgM antibody directed against virus capsid antigen. EBV was demonstrated in lymphoreticular tissues by electron microscopy and molecular hybridization studies. Permissive EBV infection was suggested by the finding of mature virus particles and linear viral DNA in lymphoreticular tissues. Immunopathological studies demonstrated complete effacement of lymph node architecture by a marked proliferation of immunoblasts in patient 1 and infiltration and effacement of the lymph node architecture with benign-appearing histiocytes in patient 2. Atypical lymphocytes characteristic of acute EBV infection were notably absent in the peripheral blood of both patients and cytotoxic T cells, which normally lyse EBV-infected B cells, were also absent from the peripheral circulation. Our observations suggest that EBV-induced VAHS may be the result of an increased virus burden in the face of immunoregulatory cell imbalances.