OBJECTIVE: The aim of this study was to measure neutrophil function longitudinally following burn injury and to examine the relationship between neutrophil dysfunction and sepsis. BACKGROUND: Sepsis prevalence and its associated mortality is high following burn injury, and sepsis diagnosis is complicated by the ongoing inflammatory response. Previous studies have suggested that neutrophil dysfunction may underlie high infection rates and sepsis postburn; however, neutrophil dysfunction has not been thoroughly characterized over time in burns patients. METHODS: Neutrophil phagocytosis, oxidative burst capacity, and neutrophil extracellular trap (NET) generation (NETosis) were measured from 1 day to up to 1 year postburn injury in 63 patients with major burns (≥15% total body surface area). In addition, immature granulocyte (IG) count, plasma cell-free DNA (cfDNA), and plasma citrullinated histone H3 (Cit H3) levels were measured. RESULTS: Neutrophil function was reduced for 28 days postburn injury and to a greater degree in patients who developed sepsis, which was also characterized by elevated IG counts. Plasma cfDNA and Cit-H3, a specific marker of NETosis, were elevated during septic episodes. The combination of neutrophil phagocytic capacity, plasma cfDNA levels, and IG count at day 1 postinjury gave good discriminatory power for the identification of septic patients. CONCLUSION: Neutrophil function, IG count, and plasma cfDNA levels show potential as biomarkers for the prediction/early diagnosis of sepsis postburn injury and neutrophil dysfunction may actively contribute to the development of sepsis. Targeting neutrophil dysfunction and IG release may be a viable therapeutic intervention to help reduce the incidence of nosocomial infections and sepsis postburn.