To date, most studies of response to the anti-interleukin 5 agent, mepolizumab, has identified eosinophils as the main clinical biomarker of response. However, many patients with eosinophilic asthma still fail to demonstrate clinical response to mepolizumab. In this study, we evaluate the association of 26 cytokines and chemokines, including T-helper 1 (Th1)-, Th2-, Th17-related cytokines and alarmins, with response to mepolizumab. We defined clinical response to mepolizumab as a reduction in the baseline annual exacerbation rate by at least half over the one-year period following initiation of mepolizumab. Our results suggest that, asides the peripheral eosinophil count, the levels of the CC motif chemokine 22 (CCL22), IL-13, and CXCL10, but not levels of IL-5, were higher in responders. These three and IL-17F, IL-23, and IL-8 had the greatest differential between responders and nonresponders to mepolizumab. Cytokines and chemokines associated with airway eosinophilia, such as CCL22 and CXCL10, may be better predictors of clinical response to mepolizumab than IL-5, the target of mepolizumab.