BACKGROUND: A subset of asthma patients have airway pathology characterized by a thickened subepithelial basement membrane zone ("BMZ-thick asthma"). OBJECTIVES: To characterize the clinical features of BMZ-thick asthma and to determine if BMZ thickness accompanies specific patterns of inflammation in the airway epithelium. METHODS: Design-based stereology was used to quantify BMZ thickness in endobronchial biopsy tissue sections from 109 asthma patients and 41 healthy controls from the Severe Asthma Research Program-3 whose participants had undergone spirometry and gene expression profiling in airway epithelial brushings. RESULTS: The upper 90th percentile value for BMZ thickness in the healthy cohort was 2.9 µM, and 35% of the asthma cohort had values above this upper limit. Compared to BMZ-thin asthma patients, BMZ-thick asthma patients were younger and had higher blood eosinophil numbers and serum immunoglobulin E levels that were specific to animal proteins. Mean pre-bronchodilator FEV1 was significantly lower in BMZ-thick than in BMZ-thin patients, but post-bronchodilator FEV1 was not. Upregulation of genes signifying interleukin-13 activation and presence of mast cells were evident in epithelial brushings in BMZ-thick patients, but gene signatures for activation by interferon gamma or interleukin-17 were not. CONCLUSIONS: A thickened BMZ marks a subset of younger asthma patients characterized by higher IgE levels to animal aeroallergens and by increased bronchomotor tone occurring in the context of airway epithelial cells activated by interleukin-13 and infiltrated by mast cells.