During chronic P. aeruginosa lung infection, a subset of patients develop an antibody response that is able to inhibit complement-mediated killing of their cognate strain. These ‘cloaking antibodies’ [cAb] were found to be IgG2 specific to O-antigen lipopolysaccharide [LPS], and are correlated with worse disease outcomes in patients with bronchiectasis. These cAb blocked access of serum complement factors to the bacterial outer membrane thus inhibiting pore-forming lysis of P. aeruginosa in a titre and affinity dependent manner. In light of this finding, three patients with chronic multi-drug resistant P. aeruginosa infections underwent plasmapheresis as a salvage therapy to deplete cAb which successfully ameliorated patient outcomes through reducing the P. aeruginosa burden up to 15 months post-treatment (1,2). Interestingly however, CF isolates of P. aeruginosa are noted to down-regulate O-antigen expression whilst another form of LPS, known as common polysaccharide antigen [CPA], is characteristically maintained (3). Despite the conservation of this key LPS antigen its role in cAb is still uncharacterised. This investigation found that serum IgG and IgA responses to CPA were elevated in 90.9% and 77.3% of sera from a cohort of forty-four P. aeruginosa colonised patients with cystic fibrosis, respectively. Further, 68.2% (n = 40/63) of patients were colonised with CPA-expressing isolates, where 22.2% of isolates (n = 14/63) expressed CPA as the sole form of LPS. Serum sensitivity assays on cognate isolates confirmed that six patients’ sera had the ability to significantly inhibit the serum bactericidal killing of P. aeruginosa. This investigation demonstrates for the first time that the mechanism of cAb may not be exclusive to O-antigen-antibody interactions, demonstrating the potential to occur against broader antigens.