While EBV establishes as infection that persists for life in almost all humans, it is rare for it to be associated with chronic or recurrent disease. Most EBV infections are either sub-clinical or associated with a transient episode of infectious monomucleosis. Chronic or recurrent infections are known to occur individuals with congenital or acquired immunodeficiency states including young boys with the x-linked lymphoproliferative disorder, transplants recipients, and AIDS patients. Over the past two decades there have been isolated reports of EBV associated disorders arising spontaneously in individuals with no recognized risk factors. In the early 1980?s we began to study individuals referred for this type of disorder. To date, we have studied in detail about 15 such individuals ranging in age from 2-36. In addition to prolonged and repeated clinical observations of these individuals numerous studies were undertaken to define the level of their immune competence, to ascertain the role, if any, played by EBV, and to develop rational therapeutic approaches. Nearly all subjects proved to possess demonstrable and evolving immune deficiency characterized largely by immunoglobulin deficiency, cutaneous anergy, and expansion of lymphocyte subsets bearing activation markers. A role has been ascribed to EBV in several of these patients by virtue of the typical onset of illness in some of them in association with an acute mononucleosis-like syndrome. IgM seroconversion was witnessed in three instances. Most of the subjects evolved markedly elevated IgG antibodies to EBV VCA, and EA while EBNA antibodies where low or absent. In situ hybridizations or Southern blot hybridizations were positive in tissues available from four of the patients. Although a role for EBV was suspected in the pathogenesis of these chronic lymphoproliferative disorders, three key observations implied that other mechanisms are dominating. The first is that the peripheral blood and lymphoid tissues of these patients largely contained mixed populations of reactive T-cells and not EBV-transformed B cells as seen in AIDS patients and transplant recipients. By marker studies, the disorders were truly polycloncal. Second, most of the patients showed objective signs of immunopathology. Cutaneous vasculitis was seen in two, veitis in one, cerebral vasculitis on one, and chronic polyneuropathy in three patients. Third, the patients generally did not respond to prolonged empiric courses of antiviral drugs. Rather, they demonstrate consistent, albeit transient, responses to immunosuppressive therapy. In some instances, prednisone dosage could be spared with use of cytotoxic drugs. Inevitably, several patients escaped effective immune suppression and went on to die of aggressive polyclonal lymphoproliferation. One patient progressed to a monoclonal lymophoma and died two part year. Five patients are still under active follow-up.