RATIONALE: Recurrent pulmonary exacerbations are associated with progressive lung disease in cystic fibrosis (CF). Current definitions of an exacerbation, although not precisely defined, include new/worsening symptoms, declining lung function, and/or changing radiological appearance. Early diagnosis of exacerbations by rapid non-invasive means should expedite therapeutic intervention, thereby minimising lung damage. OBJECTIVES: To identify biomarkers of lung exacerbation for point-of-care monitoring of CF lung disease progression. METHODS: Saline-induced sputum was collected from CF adults with an exacerbation and requiring hospitalisation (forced expiratory volume in one second (FEV₁) <60%), a subset of these adults at hospital-discharge, CF children with stable disease and preserved lung function (FEV₁ >70%), and controls (FEV₁ >80%). Sputum was arrayed by 2-dimensional electrophoresis and differentially expressed proteins identified by proteomic analysis. MEASUREMENTS AND MAIN RESULTS: Sputum profiles from CF adults with an exacerbation were characterised by extensive proteolytic degradation and influx of inflammation-related proteins with some CF adults approaching a 'healthy' protein profile after hospitalisation. Two CF children showed profiles and biomarker expression resembling adults with an exacerbation. Levels of differentially expressed myeloperoxidase, cleaved alpha-1-antitrypsin, IgG degradation, interleukin-8, and total protein concentration, together with their correlation to FEV₁, were statistically significant. Statistical correlation analyses indicated that changes in myeloperoxidase expression and IgG degradation were the strongest predictors of FEV₁. CONCLUSIONS: We identified extensive protein degradation and differentially expressed proteins as biomarkers of inflammation relating to pulmonary exacerbations. Prediction of exacerbation onset and more precise evaluation of the extent of resolution with treatment could be achieved by including biomarkers in standard assessment.