BACKGROUND: Neutrophil acts as a double-edged sword in the immune system. We hypothesized that an elevated neutrophil granule protein level is associated with sepsis-associated lymphopenia (SAL). METHODS: We enrolled 61 patients with sepsis admitted to the Department of Critical Care Medicine of Peking Union Medical College Hospital between May 2022 and October 2023 in this study. Clinical and immunological parameters were recorded. Levels of neutrophil granule proteins, including myeloperoxidase (MPO) and neutrophil elastase (NE), and pyroptosis factors were examined. RESULTS: Levels of neutrophil granule proteins (MPO, 82.9 vs. 175.3, CONCLUSION: Increased levels of neutrophil granule proteins were significantly associated with SAL incidence, and a significant relationship between neutrophil granule proteins and the pyroptosis pathway of CD4 CLINICAL TRIAL REGISTRATION: chictr.org.cn identifier ChiCTR-ROC-17010750.