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Asthma heterogeneity complicates the search for targeted treatment against airway inflammation and remodeling. We sought to investigate relations between eosinophilic inflammation, a phenotypic feature frequent in severe asthma, bronchial epithelial transcriptome, and functional and structural measures of airway remodeling. We compared epithelial gene expression, spirometry, airway cross-sectional geometry (computed tomography), reticular basement membrane thickness (histology), and blood and bronchoalveolar lavage (BAL) cytokines of <i>n</i> = 40 moderate to severe eosinophilic (EA) and non-eosinophilic asthma (NEA) patients distinguished by BAL eosinophilia. EA patients showed a similar extent of airway remodeling as NEA but had an increased expression of genes involved in the immune response and inflammation (e.g., <i>KIR3DS1</i>), reactive oxygen species generation (<i>GYS2</i>, <i>ATPIF1</i>), cell activation and proliferation (<i>ANK3</i>), cargo transporting (<i>RAB4B</i>, <i>CPLX2</i>), and tissue remodeling (<i>FBLN1</i>, <i>SOX14</i>, <i>GSN</i>), and a lower expression of genes involved in epithelial integrity (e.g., <i>GJB1</i>) and histone acetylation (<i>SIN3A</i>). Genes co-expressed in EA were involved in antiviral responses (e.g., <i>ATP1B1</i>), cell migration (<i>EPS8L1</i>, <i>STOML3</i>), cell adhesion (<i>RAPH1</i>), epithelial–mesenchymal transition (<i>ASB3</i>), and airway hyperreactivity and remodeling (<i>FBN3</i>, <i>RECK</i>), and several were linked to asthma in genome- (e.g., <i>MRPL14</i>, <i>ASB3</i>) or epigenome-wide association studies (<i>CLC</i>, <i>GPI</i>, <i>SSCRB4</i>, <i>STRN4</i>). Signaling pathways inferred from the co-expression pattern were associated with airway remodeling (e.g., TGF-β/Smad2/3, E2F/Rb, and Wnt/β-catenin).