BACKGROUND AND OBJECTIVES: Although immunochemotherapy has been reported to be an effective initial treatment for patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), the long-term outcome of these patients remains unknown. The main purpose of this study was to determine the outcome of the EBV-HLH patients treated between 1992 and 2001. DESIGN AND METHODS: During this period, a total of 78 EBV-HLH patients were consecutively registered in 3 separate studies. The rates of initial response, reactivation, and survival as well as causes of death were analyzed. The outcome of the patients who received hematopoietic stem cell transplantation was also studied. RESULTS: With a median follow-up of 43 months, clinical reactivation was noted in 13 patients (19.4%) and a total of 12 patients needed hematopoietic stem cell transplantation, of whom 9 are alive and well. There had been 19 deaths: early deaths were due to hemorrhages and infections (n=11), while late deaths were related to late reactivation (n=4), transplant-associated causes (n=3) and secondary leukemia (n=1). Overall, after a median follow-up of 43 months, 59 (75.6%) of the 78 patients are alive and well. INTERPRETATION AND CONCLUSIONS: The majority of successfully treated EBV-HLH patients have a good outcome and remain disease-free.