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Background Pleural infection is a severe and complicated disease with increasing worldwide incidence. Despite being recognised for decades, currently there is only one set of guidelines for pleural infection management. Clinical outcomes remain poor and validated biomarkers to predict disease progression or response to treatment are not available. In addition to Plasminogen Activator Inhibitor 1 (PAI-1) and Soluble Urokinase Plasminogen Activator Receptor (suPAR), neutrophil elastase (NE) recently emerged as a potential fibrinolytic deficiency biomarker as it has been suggested to inhibit fibrinolysis by degrading plasminogen and thereby increasing the likelihood of septations.Aim To investigate the effect of neutrophil elastase and neutrophil extracellular traps (NETs) on intrapleural fibrinolytic deficiency using fresh specimens prospectively collected from pleural infection patients at baseline and post-intrapleural fibrinolytic treatment. Also to explore the potentiality of NE and NETs as biomarker for disease management and patient stratification.Results We found a negative correlation between the protein level of intrapleural neutrophil elastase and plasminogen ( r= -0.4214, p= 0.0178*). Pharmacological inhibition of NE reduced plasminogen degradation (~24% reduction, p= 0.0372*), confirming the involvement of NE in the fibrinolytic deficiency. Pleural infection patients with significantly higher levels of NETs (NE-DNA) in their pleural fluid were more prone to develop septations (p= 0.0032**) and showed poorer one-year survival rate (p= 0.00075***). Cox regression revealed that each 1000-unit increase in NETs was associated with a hazard ratio of 1.16 (95% CI:1.02–1.32, p= 0.0168*). Intrapleural fibrinolytic treatment promotes fibrinolytic potential and reduces the level of NETs and neutrophil-derived proteins such as NE in pleural fluid.Conclusion In conclusion, our data demonstrates the contribution of NE and NETs in intrapleural fibrinolytic deficiency. Both pose as potential important targets for disease management.