We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children <15 years old) with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The study group received a median cumulative dose of 1,500 mg/m2 etoposide (range, 0-14,550 mg/m2), with a median follow-up period of 44 months (range, 20-88 months) from the diagnosis. Only 1 patient, who received 3150 mg/m2 etoposide, developed therapy-related acute myeloid leukemia (t-AML), at 31 months after diagnosis. Excluding 9 patients who underwent hemopoietic stem cell transplantation during the course of treatment, the prognosis was poorer for those patients who received less than a 1,000 mg/m2 cumulative dose of etoposide. Our results indicate that the risk of etoposide-related t-AML is low. An appropriate dosage of etoposide for the treatment of EBV-HLH would be in the range of 1,000 to 3,000 mg/m2. However, even at these doses, care must be taken to prevent the rare risk of t-AML.