Pseudomonas aeruginosa is the principle pathogen implicated in progressive and recurrent respiratory infections in cystic fibrosis (CF) and bronchiectasis. These infections are extremely difficult to eradicate, leading to overall poorer quality of life and increased disease severity. Recently, impaired serum-mediated killing of P. aeruginosa was associated with increased severity of respiratory infections in bronchiectasis patients. This inhibition was mediated by O-antigen-specific IgG2 antibodies. It was hypothesised that IgG2 inhibited serum-mediated killing by binding to O-antigen to create a physical blockade, preventing normal complement access to the bacterial membrane. While it has been suggested these ‘inhibitory antibodies’ may also play a role in CF patients, this remains to be elucidated. Previous findings from our laboratory demonstrated inhibition by IgG2 acted in a titre-dependent manner. Here we investigate the prevalence of inhibitory antibodies in CF patients and characterise the mechanisms underlying inhibition. IgG2 titres were measured in 75 serum samples obtained from patients with CF against eight P. aeruginosa serotypes. To confirm the inhibitory capacity of serum, serum bactericidal assays (SBA) were performed. We identified 24 of 75 patients who had serum that inhibited killing of P. aeruginosa. Interestingly, in a small number of patients with low IgG2 titres, increased antibody affinity appeared to mediate inhibition of killing. Moreover, in other patients with low IgG2 titre but inhibited serum killing, we found that high titres of lipopolysaccharide (LPS)-specific IgA inhibited killing of P. aeruginosa, suggesting an inhibitory role for IgA.