To explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH). Clinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed. The child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died. The latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.