Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease. This case report describes a secondary chronic myelogenous leukemia (CML) in a nine-year-old male after treatment with a combination of etoposide (VP16), steroids and cyclosporin for HLH. VP16 can potentially induce leukemia, and single nucleotide polymorphisms may be involved in the pathogenesis of CML. We speculate that genetic backgrounds combined with chemotherapeutic drugs lead to secondary CML. This case report alerts physicians to the importance of genetic screening and the rare side effects of VP16 in children with HLH.