Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis and airway smooth muscle mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor (mIL-6R), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6R (sIL-6R) to stimulate membrane receptor-deficient cells; a process called trans-signaling. We discovered that primary human airway smooth muscle (ASM) cells do not express mIL-6R and therefore investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6R to activate STAT3 with no differences observed between cells from asthmatics compared to controls. Further analysis revealed that IL-6, alone or with sIL-6R did not induce release of matrix stimulating factors (including connective tissue growth factor, fibronectin or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6R, IL-6 increased eotaxin and VEGF release, and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatics. As levels of sIL-6R are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.