EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as a systemic illness characterized by clonal proliferation of EBV-infected T or NK cells. We prospectively enrolled 108 nonimmunocompromised patients with this disease (50 men and 58 women; median onset age, 8 years; age range, 1-50 years) evidenced by expansion of EBV(+) T/NK cells in the peripheral blood; these were of the T-cell type in 64 cases and of the NK-cell type in 44, and were clinically categorized into 4 groups: 80 cases of chronic active EBV disease, 15 of EBV-associated hemophagocytic lymphohistiocytosis, 9 of severe mosquito bite allergy, and 4 of hydroa vacciniforme. These clinical profiles were closely linked with the EBV(+) cell immunophenotypes. In a median follow-up period of 46 months, 47 patients (44%) died of severe organ complications. During the follow-up, 13 patients developed overt lymphoma or leukemia characterized by extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Fifty-nine received hematopoietic stem cell transplantation, 66% of whom survived. Age at onset of disease (≥ 8 years) and liver dysfunction were risk factors for mortality, whereas patients who received transplantation had a better prognosis. These data depict clinical characteristics of systemic EBV(+) T/NK-LPD and provide insight into the diagnostic and therapeutic approaches for distinct disease.