Avian influenza A(H5N6) keeps evolving, causing outbreaks in birds and sporadic infections in human. Here we report a fatal pediatric infection caused by a novel reassortant H5N6 virus. The patient was an obese 9-year-old girl. She initiated with fever and cough, then developed pneumonia, acute respiratory distress syndrome (ARDS) and respiratory failure. Lower respiratory tract aspirates and anal swabs were serially taken till the patient’s death. Viral isolation, genome sequencing and phylogenetic analysis were conducted. A novel reassortant H5N6 virus was isolated from the patient. Except the PA gene, all other 7 genes of the virus belonged to H5N6 genotype A (S4-like virus). The PA gene was probably obtained from Eurasian waterfowl influenza viruses. The H5N6 virus was consistently detected from the patient’s respiratory samples till the 17 day after symptom onset, but not from anal swabs or urine sample by real-time reverse transcription polymerase chain reaction (RT-PCR). Significantly elevated (32-fold) serum antibodies to H5N6 virus were observed during the patient’s course of disease. Aside from the identified novel reassortant H5N6 viral strain, obesity, delayed confirmation of etiology and specific antiviral treatment, and prolonged virus shedding could have contributed to the poor clinical outcome.This article is protected by copyright. All rights reserved.