Biologic therapies targeting IL-5 or its receptor reduce eosinophilia and exacerbations in asthma. Breakthrough eosinophilic attacks are usually considered biologic failure. We report 2 patients with severe asthma receiving mepolizumab or benralizumab who developed relapsing hypereosinophilia associated with Pseudomonas aeruginosa airway infection. Case 1 was a 71-year-old woman in Canada with severe eosinophilic asthma and COPD overlap whose eosinophils suddenly rebounded to 1,400 cells/μL during an acute exacerbation while on mepolizumab, coinciding with P aeruginosa infection and resolving after antibiotic treatment.