Alterations in airway smooth muscle structure and function are key to the pathogenesis of asthma and may underlie increased airway narrowing and airways hyperresponsiveness. The mechanisms underlying these changes in smooth muscle phenotype and function are currently largely unknown. Here, we report a role for WNT-5A overexpression by airway smooth muscle from asthma patients and link this to the alterations in airway smooth muscle structure and function seen in this disease. Airway smooth muscle expressed a number of WNT ligands, of which WNT-5A was among the most abundant. mRNA and protein expression of WNT-5A was increased in airway smooth muscle from asthma patients. Moreover, a single nucleotide polymorphism in the WNT-5A gene was found to associate with asthma susceptibility. WNT-5A expression in lung tissue and bronchoalveolar lavage fluid was inducible following in vivo allergen exposure. Further, in vitro exposure of cultured human airway smooth muscle cells to pro-inflammatory cytokines and growth factors including IL-1b, PDGF-AB and TGF-b1 induced mRNA and protein expression of WNT-5A. Autocrine WNT-5A production was found to regulate several functions of the airway smooth muscle, including cytokine production, cell proliferation, and extracellular matrix protein production. Collectively, we identify a novel role for WNT-5A in asthma, and indicate that WNT-5A overexpression by the airway smooth muscle may contribute to the alterations in airway smooth muscle structure and function that are characteristic of asthma.