Objectives: To characterize the rate of decline of forced expiratory volume in 1 second (FEV1) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV1 decline. Study design: The rate of decline in FEV1% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression. Results: Mean (±SD) baseline FEV1% predicted was 88.4% ± 20.5% for 6- to 8-year-olds (n = 1811), 85.3% ± 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% ± 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV1% predicted/year was -1.12, -2.39, and -2.34, respectively. High baseline FEV1 and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups. Conclusions: This study identifies risk factors for FEV1 decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV1.