Background: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, the objectives of this study were to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease. Methods: Prospective 3-year multi-centre observational study of repeated LCI measurement at time of clinical review in CF patients >5yrs, delivered using a rapid wash-in system. Results: 112 patients completed at least one LCI assessment, and 98 (90%) were still under follow-up at study end. Median (IQR) age 14.7 (8.6-22.2) years, mean (SD) FEV1 z score – 1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within six months, mean (limits of agreement) change in LCI was 0.9 (-18.8 to 20.7)%. A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. Median total test time was under 19 minutes. Conclusions: Most CF patients with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.