Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.