Abstract Background Weight loss indicates a poor prognosis in cystic fibrosis (CF). We hypothesised that fat-free mass (FFM) depletion and increased systemic inflammation would be associated with increased cellular proteolysis during an exacerbation of the respiratory symptoms. Patients were studied prospectively from the beginning of treatment with antibiotics when admitted to the Adults CF Centre. Methods Twenty six patients with CF were studied at the start and end of antibiotic treatment and 2 weeks later. Mean (95% CI) FEV 1 when clinically stable was 54.1 (44.5, 62.6)% predicted. Urinary excretion of Pseudouridine (5-ribosyluracil, PSU) was determined as an indicator of cellular protein breakdown. Body composition was assessed by dual energy X-ray absorptiometry (DXA). Results Patients had increased concentrations of PSU at all assessments ( p<0.01). Those with a low FFM had greater PSU (ratio to FFMI) than those with a normal FFM at all assessments. At the start of treatment, PSU was related to FFM, C-reactive protein (CRP) ( p<0.05) and tumour necrosis factor (TNF)α soluble receptors (sr) I and II ( p<0.01). Circulating inflammatory mediators were greater in patients than in healthy subjects at all assessments. Conclusion Increased protein breakdown is associated with a low FFM and increased systemic inflammation and it may be a contributory mechanism of poor weight preservation in CF.