Cystic Fibrosis (CF) pulmonary exacerbations (PEx) are associated with accelerated lung disease progression and decreased survival. There is variability in the frequency of PEx events between people with CF (pwCF). The pathophysiological mechanisms underlying frequent PEx have not been previously explored. We hypothesised that during a PEx the sputum proteome would differ between pwCF who have a history of frequent PEx compared to those with infrequent PEx. Sputum was obtained from CF adults receiving intravenous (IV)-antibiotic treatment for a PEx on day 0 (D0) and between day 3-5 (D5) of IVs. Participants were identified as infrequent exacerbators or frequent exacerbators based on the number of PEx in the previous year (<2 or ?2). Shotgun proteomic analysis of sputum was performed by liquid chromatography-mass spectrometry. Protein validation was carried out western blot and ELISA. Of the 360 proteins identified, 23 were significantly differentially enriched on D0 and 34 were significantly differentially enriched on D5 between infrequent and frequent exacerbators. The majority had a higher abundance in infrequent exacerbators (n=18 on D0 and n=23 on D5). Proteins enriched in infrequent exacerbators had innate host defence functions such as antiprotease, antimicrobial and immunomodulatory activity whereas proteins enriched in frequent exacerbators were intracellular or exosome derived. These data suggest that frequent exacerbators have a greater imbalance in their airway innate host protein defences, which may result in an environment that is more susceptible to injury and with reduced capacity to resolve inflammatory responses during PEx.