Small airway disease is thought to contribute significantly to functional impairment caused by asthma. Functional evidence of airway-parenchyma uncoupling in asthma, such as loss of deep breath bronchodilator effect in bronchoconstrictive episodes and enhanced airway closure, has been previously demonstrated. Elastic fibers are essential to maintain adequate elastic recoil of the lungs. In this study, we hypothesized that alveolar attachments could be abnormal and that elastic fibers could be damaged in the distal lungs of patients with fatal asthma. For this purpose, we measured the number of abnormal alveolar attachments and quantified the content of elastic fibers in the adventitial layer of small airways and in the peribronchial and distal alveolar septa of 15 patients who died of asthma (FA) and 9 control subjects (CTRL). Our data (geometric mean [range]) showed an increased proportion of abnormal alveolar attachments per centimeter of basement membrane perimeter in fatal asthma (FA, 0.18 [0.03-4.00]; CTRL, 0.00 [0.00-0.12]; p < 0.001) and decreased elastic fiber content in the small airway adventitial layer (FA, 4.08 [2.22-11.46] microm; CTRL, 6.79 [5.62-10.0] microm; p = 0.01) and in the peribronchial alveoli (FA, 1.08 [0.46-1.91] microm; CTRL, 1.81 [1.22-1.74] microm; p = 0.003), but not in the distal alveoli. We propose that structural alterations at the peribronchiolar level might contribute to the pathogenesis of some functional abnormalities observed in patients with severe asthma.