Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal hematological syndrome that causes a disturbance of the immune system. Overall mortality of HLH is greater than 50% and the majority of patients who die do so within the first 8 weeks of chemotherapy treatment. To find clinical parameters relating to high-risk HLH patients, this study examined associations between an early fatal outcome and potential prognostic clinical factors and laboratory findings on admission. Eighty-nine pediatric HLH patients were prospectively recruited in Children's Hospital No. 1, Ho-Chi-Minh City, Vietnam, during the period from January 2010 to August 2012. Associations between early fatal outcome and clinical and laboratory findings, including a cerebrospinal fluid examination and virological test on admission, were examined. During the 8-week therapy, 25 (28%) HLH patients died. Persistent fever (>2 weeks), severe thrombocytopenia (<75 × 10(9)/L), hyperbilirubinemia, and prolonged activated partial thromboplastin time (APTT) (>33 sec) were significant risk factors of early fatal outcome. Multivariate logistic regression analysis revealed that thrombocytopenia and prolonged APTT (P for trend was 0.054 and 0.013, respectively) were independently associated with the early fatal outcome. Persistent fever, severe thrombocytopenia, hyperbilirubinemia, and prolonged APTT on admission will be useful and practical predictors to determine high-risk HLH patients.