Rationale: Sputum neutrophil elastase and serum desmosine, a linked marker of endogenous elastindegradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.Methods: This was a single-centre prospective cohort study using the TAYBRIDGE registry in Dundee, UK. 433 patients with HRCT-confirmed bronchiectasis provided blood samples for desmosine measurement and 381 provided sputum for baseline elastase activity measurements using an activity based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3-years.Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r=0.49,p<0.0001) and also correlated with MRC dyspnoea score (r=0.34,p<0.0001), FEV1 % predicted (r=-0.33,p<0.0001) and the radiological extent of bronchiectasis (r=0.29,p<0.0001). During 3-years follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (p<0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV1 decline (beta coefficient -0.139,p=0.001). Elastase showed good discrimination for severe exacerbations AUC 0.75 (0.72-0.79) and all-cause mortality AUC 0.70 (0.67-0.73) Sputum elastase activity increased at exacerbation (p=0.001) and was responsive to treatment with antibiotics.Desmosine was correlated with sputum elastase (r=0.34,p<0.0001), and was associated with risk of severe exacerbations HR 2.7 (1.42-5.29),p=0.003, but not lung function decline.Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.