BACKGROUND & AIMS: Malnutrition is associated with poorer outcome in cystic fibrosis (CF). This follow-up study aimed to document nutritional status changes, including fat-free mass (FFM), in adults with CF; and to identify predictors of FFM loss. METHODS: Fifty-eight non-transplanted CF adults (mean ± SD forced expiratory volume in one second (FEV1) 63.7 ± 21.4%predicted; mean ± SD age 30.3 ± 7.7years at baseline) were studied at baseline and 3.6 ± 0.4 years later. Body composition was measured using dual-energy X-ray absorptiometry. At follow-up, blood was analysed for interleukin-6 and tumour necrosis factor-α (TNF-α) on three occasions over six months and averaged for each participant. Associations with annual percentage change in FFM (ann%ΔFFM), including cytokines, CF genotype and annual change in FEV1%predicted (annΔFEV1%), were determined. RESULTS: Mean FFM was 49.5 ± 8.8 kg at baseline and 49.6 ± 8.9 kg at follow-up (p = 0.66). Ann%ΔFFM ranged from -2.0 to +3.6%. FEV1%predicted declined by 1.2 ± 2.4% per year. Forty percent of participants had elevated average interleukin-6 levels. Ann%ΔFFM was negatively correlated with interleukin-6 levels (rho -0.34, p = 0.008), but not TNF-α or annΔFEV1%. F508DEL homozygote or heterozygote participants had greater FFM loss than those carrying no F508DEL allele (p = 0.01). CONCLUSION: Higher serum interleukin-6 and presence of the F508DEL mutation, but not TNF-α, were associated with FFM loss in adults with CF.