In clinical trials, the two anti-IL-5 monoclonal antibodies (mAbs, mepolizumab and reslizumab) that are approved to treat severe eosinophilic asthma, reduce exacerbations by approximately 50-60%.To observe response to anti-IL-5 mAbs in real-life clinical setting, and to evaluate predictors of sub-optimal response.In four Canadian academic centres, pre-defined clinical end-points in 250 carefully characterised moderate-to-severe asthmatics were collected prospectively to assess response to the two anti-IL-5 mAbs. Sub-optimal responses was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (ACQ) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders were assessed based on reduced lung function by 25% or any increase in MCS/ACQ. A representative sub-set of 39 patients were evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.Sub-optimal responses were observed in 42.8% (107/250) patients treated with either mepolizumab/reslizumab. Daily prednisone requirement, sinus disease, and late-onset asthma diagnoses were the strongest predictors of sub-optimal response. Asthma worsened in 13% (34/250) of these patients. Majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of sub-optimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.A significant number of patients who meet currently approved indications for anti-IL5 mAbs show sub-optimal response to them in real-life clinical practice. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement-activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.