Objective To improve the diagnosis and treatment outcomes of refractory Epstein-Barr virus (EBV) associated hemophagocytic lymphohistiocytosis(EBV-HLH), by analyzing and summarizing the clinical manifestations, diagnosis and treatment of the children with refractory EBV-HLH. Methods The clinical data of 3 refractory EBV-HLH patients were analyzed retrospectively, and the related literatures were reviewed simultaneously by analyzing and summarizing the clinical data with refractory EBV-HLH. Results Three patients were all young infant, with recurrent fever accompanied with hepatosplenomegaly as primary manifestations, and with a negative family history.No pathologic known HLH related gene mutations were found.EBV-DNA was obviously increased on diagnosis, with leukopenia and neutropenia.Treatment effect of HLH-94 protocol was not good in these 3 patients.During treatment there were still intermittent fever.And there was an outbreak during chemotherapy, accompanied by sharply increased levels of IFN-γ and IL-10.Plasma EBV-DNA was persistent or recurrent positive.HLH progressed rapidly after the out break of the disease.DEP protocol and plasmapheresis therapy was ineffective.Patients died due to the complicated gastrointestinal bleeding and multiple organ failure. Conclusions Treatment outcomes with chemotherapy might be disappointing in patients with refractory EBV-HLH among young infants, with obviously increased EBV-DNA leukopenia and neutropenia on diagnosis.Disease outbreak could occur during treatment.EBV-DNA titer and cytokine levels are of great value to the early diagnosis of HLH activation.Early identification of such patients, and timely hematopoietic stem cell transplantation were really important to improve the prognosis. Key words: Epstein-Barr virus; Hemophagocytic lymphohistiocytosis; Child