Background: Tobacco smoke exposure is a major risk factor for the health of children and adolescents with CF. In this study, we assess whether cessation of smoke exposure is associated with improved outcomes in this population. Methods: We used annualized and encounter-based data from the U.S. CF Foundation Patient Registry (2006-2018) on all individuals born 1998-2010. The analytical sample included those who ever reported second-hand smoke exposure (daily or weekly), ever lived with a smoker, or ever reported smoking themselves. We used non-linear mixed models for pulmonary exacerbations and linear mixed models for ppFEV1 and BMI as a function of ceased exposure. Results: The sample included 3,633 individuals contributing 19,629 person-years. Cessation of smoke exposure reduced the odds of a pulmonary exacerbation in 12 months by 17% (OR 0.83, p < 0.001) in the first year of cessation, with an additional 6% decrease (OR 0.94, p = 0.003) for each additional year of cessation. Cessation was associated with improvements in ppFEV1 and BMI: 0.7% ppFEV1 increase (p < 0.001) in the first year of cessation and 0.4% increase (p = 0.001) for each additional year of cessation; 1% increase in BMI percentile (p < 0.001) in the first year of cessation plus 0.4% increase (p = 0.009) for each additional year. Three years of cessation reduce the predicted probability of a pulmonary exacerbation in 12 months by 8% and improve ppFEV1 and BMI by 2%. Conclusion: Eliminating smoke exposure may reduce pulmonary exacerbations and improve respiratory and nutritional outcomes in children and adolescents with CF. Both smoking cessation and exposure prevention should be prioritized in pediatric CF care.