Cystic fibrosis (CF) is one of the most prevalent autosomal recessive condition to affect Caucasian populations. It is a multi-system disease which results in a myriad of medical complications for the patient. The difficulties associated with CF often is due to chronic pulmonary infections with Pseudomonas aeruginosa. Recently, impaired serum-mediated killing of P. aeruginosa was described in patients with bronchiectasis. IgG2 specific to the O-antigen side chains of LPS was identified as the inhibitory factor in serum. The ‘inhibitory antibodies’ were present in 20% of patients chronically infected with P. aeruginosa. Importantly, the presence of inhibitory antibodies correlated with increased respiratory infections and disease severity, evident by respiratory function. It is proposed IgG2 exerts its role as an inhibitor in serum by binding to O-antigen to create a physical blockage, preventing the access of protective antibodies and the membrane attack complex. Here, we investigated the presence of inhibitory antibodies in a new CF cohort, complementing the findings of Wells et al., 2014, and expanding the scale of impaired serum killing to other chronic lung diseases. We established our CF cohort predominately had O-antigen specific antibody to P. aeruginosa serotypes, O1, O3, O6 and O11. Further, we found that over ~34% (26/75) of patients had antibody which impaired bactericidal activity of sera. Interestingly, titre alone was not sufficient to predict serum inhibition, with affinity of antibodies also important. 2/25 patients with impaired killing did not produce high IgG2 titres to O-antigen, yet could still inhibit. Here, O-antigen specific IgA was the inhibitory factor in impaired serum. These findings have improved our understanding of the scope, mechanism and mode of inhibitory antibodies. Importantly, this will aid in the development of early diagnostics and lead to the improvement of targeted immunotherapies.