*JA and PB are co-senior authorsBackground: Th2 and Th17 cytokine-dependent inflammatory pathways are potential therapeutic targets in severe asthma. The extent of the activity of these two pathways in individual patients is unclear.Objective: To develop gene expression signatures of Th2 and Th17 cytokine activity in asthmatic airways and assess their relationships to airway pathophysiology, clinical disease expression, and biomarkers of cytokine activity.Methods: Th2 and Th17 cytokine gene expression metrics were developed in vitro in primary human bronchial epithelial cells and used to interrogate the activity of these pathways in endobronchial tissue from patients with clinically well-characterised asthma across a spectrum of severity (n=51).Results: We identified three clusters of cytokine gene expression in asthmatic airways: Th2-high, Th17-high and Th2/17-low. Th2-high and Th17-high patterns were mutually exclusive in individual patients, and were inversely correlated. However Th2 and Th17 signatures were both associated with airway eosinophilia. The Th17 signature was only detected in patients taking inhaled corticosteroids (ICS) while Th2-high and Th2/17-low patterns were present in ICS users and non-users. Only the Th2/17-low signature was associated with non-eosinophilic pathology.Conclusion: Patients with severe asthma may have either a Th2-high, Th17-high or Th2/17-low pattern of airway gene expression. Low levels of blood and sputum eosinophilia predict a Th2/17-low molecular phenotype, but all three molecular phenotypes may be associated with eosinophilic disease, which may have implications for therapeutic strategies targeting inflammatory cytokines.