Rationale: Airway mucus plugs, composed of mucin glycoproteins mixed with plasma proteins, are an important cause of airway obstruction in acute severe asthma, and they are poorly treated with current therapies. Objectives: To investigate mechanisms of airway mucus clearance in health and in acute severe asthma. Methods: We collected airway mucus from asthmatics and non-asthmatic controls using sputum induction or tracheal aspiration. We used rheological methods complemented by centrifugation-based mucin size profiling and immunoblotting to characterize the physical properties of the mucus gel, the size profiles of mucins, and the degradation products of albumin in airway mucus. Results: Repeated ex-vivo measures of size and entanglement of mucin polymers in airway mucus from non-asthmatic controls showed that the mucus gel is normally degraded by proteases and that albumin inhibits this degradation. In airway mucus collected from asthmatics at different time points during acute asthma exacerbation, protease-driven mucus degradation was inhibited at the height of exacerbation but restored during recovery. In immunoblots of human serum albumin digested by neutrophil elastase and immunoblots of airway mucus, we found that albumin was a substrate of neutrophil elastase and that products of albumin degradation were abundant in airway mucus during acute asthma exacerbation. Conclusions: Rheological methods complimented by centrifugation-based mucin size profiling of airway mucins in health and acute asthma reveal that mucin degradation is inhibited in acute asthma, and that an excess of plasma proteins present in acute asthma inhibit the degradation of mucins in a protease dependent manner. These findings identify a novel mechanism whereby plasma exudation may impair airway mucus clearance.