Five patients with familial erythrophagocytic lymphohistiocytosis (FEL), aged 6 weeks to 3 years, were treated with VP-16-213. The drug dosage ranged from 100 to 200 mg/m2 administered biweekly until remission was achieved, and then at 1- to 3-week intervals as maintenance therapy. Intrathecal methotrexate was given to two patients with central nervous system involvement. All patients attained remission. Systemic relapses often ensued in all patients when VP-16-213 was delayed because of myelosuppression, or after attempts to lengthen the treatment interval, but they initially responded again to a more intensive chemotherapy schedule. To date, four of the patients died from disseminated disease and terminal infections 15 to 20 months from the time of diagnosis. One child is alive and well 20 months from diagnosis. Three of the dead children had become refractory to the drug. Our observations show that VP-16-213 induces remissions and prolongs survival in FEL. However, since the patients eventually become refractory to the drug and die of the disease, additional forms of therapy are required to improve the outlook of affected children.