During chronic P. aeruginosa lung infection, a subset of patients develop an antibody response that is able to paradoxically inhibit complement-mediated killing of their infecting strain. These ‘cloaking antibodies’ were found to be specific to O-antigen and are correlated with worse disease outcomes in patients with bronchiectasis, and lung transplants recipients. In light of this, plasmapheresis was conducted as a salvage therapy for three patients with chronic P. aeruginosa infection, which included the removal of patient antibody from circulation. This treatment resulted in decreased bacterial burden and as such, greatly improved patient outcomes (1, 2). However, the use of plasmapheresis to P. aeruginosa infection is imprecise, requiring the total removal of antibody including potentially beneficial immunoglobulin. In addressing this, three affinity purification methods i) O-antigen affixed polymyxin-B column; ii) O-antigen-streptavidin column, and; iii) O-antigen magnetic nanobeads were developed that selectively deplete cloaking antibody when passaged with patient sera in vitro. Selective depletion of cloaking antibody in patient serum was not only able to restore, but in certain modalities improve serum-mediated killing of P. aeruginosa in comparison to healthy, normal serum. Depletion of O-antigen-specific antibody occurred across IgG, A and IgM responses whilst maintaining antibody to P. aeruginosa outer-membrane proteins. More promisingly, this novel finding demonstrates that patient sera with cloaking antibody still maintains the ability to promote antibody-mediated serum killing of P. aeruginosa. This highlights the need to improve plasmapheresis to recirculate healthy, protective antibody to the host and in turn initiate effective and durable clearance of infection.