Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive inflammation due to abnormal immune activation. HLH occurs as an familial form caused by mutation in several genes or as an acquired form. Although it can occur in all age groups, neonatal onset HLH is very rare. We report here a 6-day-old neonate with confirmed HLH who had a fatal course in the disease process in spite of early chemotherapy. Case: A 6-day-old female neonate was transferred to our medical center because of severe thrombocytopenia, hepatosplenomegaly and persistent fever shortly after birth. She was born at 40 weeks of gestation with a weight of 3.5 kg. She presented petechiae on her face, bruises on the posterior pharyngeal wall and subcostal retraction at birth. High fever and respiratory failure continued despite treatment of empirical antibiotics and mechanical ventilation. No organisms were detected in blood, urine and CSF samples from this patient at previous institution. On physical examination at admission, there were hepatomegaly, splenomegaly and petechiae on her whole body. Laboratory findings showed pancytopenia (neutrophil count of 0.73 x 109/L, hemoglobin of 10.3 g/dL and platelet count of 24 x 109/L), elevated lactate dehydrogenase level (1,159 IU/L), and elevated c-reactive protein level (5.50 mg/dL). We tested additional laboratory workup, which showed ferritin, ＞8,000 ng/mL; fibrinogen, 60 ㎍/mL; soluble IL-2 receptor, 250,480 U/mL. Bone marrow aspiration showed increased hemophagocytic histiocytes. Because the diagnostic criteria for HLH was suitable in this patient, we performed PRF1 and UNC13D gene mutation analysis. Chemo-immunotherapy was initiated on 8 days of age according to HLH-2004 protocol, however she died on 10 days of age due to sudden severe pulmonary hemorrhage. After death, mutation in PRF1 gene (c.1136G＞A(p.Arg379Gln), heterozygous) was detected in blood sample by genetic analysis. Conclusion: Prompt diagnosis and treatment are crucial for the overall well-being and survival of patient with HLH. In the case of neonate presenting severe cytopenia, splenomegaly and uncontrolled fever in spite of treatment of broad spectrum antibioitcs after birth, HLH should be considered in the differential diagnosis.