The classic pathologic finding in patients with fatal asthma is of markedly hyperinflated lungs. This hyperinflation is the consequence of widespread plugging of the segmental and sub-segmental airways. In contrast to fatal asthma, the link between mucus plugs and airflow obstruction is not established in chronic asthma, and the role of eosinophils and their products in mucus plug formation is unknown. I hypothesize that patients with chronic asthma who have a significant number of airway mucus plugs are characterized by a low forced expiratory volume in 1s (FEV1), airway type 2 inflammation and abnormal mucin gene expression. Furthermore, I hypothesize that eosinophils play a role in mucus plugs formation. To test these hypotheses, I developed a novel bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans. I applied the score to the MDCT lung scans of 146 subjects with asthma and 22 healthy controls in the Severe Asthma Research Program, and analysed relationships between mucus plug scores, FEV1, symptoms of chronic mucus hypersecretion (CMH), treatment responses, and measures of airway inflammation. In bench studies, I used model systems of airway mucus gels to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups promote mucus plug formation. Mucus plugs were seen in 58% of subjects with asthma and in 4.5% of controls, and plugs in subjects with asthma were seen in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma FEV1 < 60% of predicted volume, 19% with FEV1 60-80%, and 6% with FEV1 > 80% (p<0.001) and also predicted residual abnormalities in FEV1 after albuterol and corticosteroid treatment. Symptoms of CMH were absent in the majority of patients with a high mucus score. A high mucus score was associated with markedly higher sputum eosinophils and EPO, and moderately higher type 2 cytokines. A high mucus score was associated with altered mucin gene expression with moderate overlap between groups. Ex vivo experimental models of mucin crosslinking demonstrated that EPO catalyses oxidation of thiocyanate by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. In conclusion, MDCT reveals an asthma phenotype characterised by mucus plugs in subsegmental airways, low FEV1, and marked type 2 inflammation, that is largely refractory to corticosteroid treatment. Overlap in mucin gene expression between groups limits their predictive value. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. I propose a novel approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs with mucolytics or inhibitors of type 2 inflammation may improve airflow in chronic severe asthma