<b><i>Background:</i></b> We examined levels of hyaluronan, a matrix glycosaminoglycan and versican, a matrix proteoglycan, in the sputum of asthmatics treated with mepolizumab (anti-IL-5 monoclonal antibody) versus placebo to evaluate the utility of these measurements as possible biomarkers of asthma control and airway remodeling. <b><i>Methods:</i></b> Patients with severe, prednisone-dependent asthma received either mepolizumab or placebo as described in a previously published randomized, double-blind, placebo-controlled study. We measured hyaluronan and versican levels by enzyme-linked immunosorbent assay in sputum collected before and after the 16-week treatment phase. Patients underwent a predefined prednisone tapering schedule if they remained exacerbation free, and sputum eosinophil percentage, asthma control questionnaire (ACQ) and spirometry were monitored. <b><i>Results:</i></b> After 6 months of mepolizumab therapy and prednisone tapering, there was a significant increase in sputum hyaluronan in the placebo group compared with baseline (p = 0.003). In contrast, there was a significant decrease in sputum hyaluronan in the active treatment group compared with placebo (p = 0.007), which correlated with improvements in percent forced expiratory volume in 1 s (FEV1%) (p = 0.001) and ACQ scores (p = 0.009) as well as a decrease in sputum eosinophils (p = 0.02). There was a nonsignificant increase in sputum versican in the placebo group (p = 0.16), a decrease in the mepolizumab group (p = 0.13) and a significant inverse correlation between versican reduction and FEV<sub>1</sub>% improvement (p = 0.03). <b><i>Conclusions:</i></b> Sputum hyaluronan values are reduced with mepolizumab therapy and correlate with improved clinical and spirometry values, suggesting this measurement may serve as a noninvasive biomarker of asthma control.