Rationale: T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5 and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. Objectives: To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Methods: Using microarray and PCR analyses of airway epithelial brushings from 42 mild-to-moderate asthmatics and 28 healthy controls, we classified asthmatics based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of: 1) cytokine expression in bronchial biopsies, 2) markers of inflammation and remodeling, 3) responsiveness to inhaled corticosteroids and 4) reproducibility on repeat examination. Measurements and Main Results: Gene expression analyses identified two evenly-sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from controls). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies, and in airway hyper-responsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis and airway mucin gene expression (all p<0.03). The lung function improvements expected with inhaled corticosteroids were restricted to "Th2-high" asthma, and Th2 markers were reproducible on repeat evaluation. Conclusions: Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of asthmatics. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies. Clinical trials registry information: ID#NCT00187499 registered at www.clinicaltrials.gov