Rationale: High-dose ibuprofen in a 4-year controlled trial slowed FEV₁ decline in young subjects with cystic fibrosis, but ibuprofen's effectiveness has not been assessed in a large group of patients treated clinically with this therapy. Objective: To assess the effect of ibuprofen therapy on FEV₁ decline in children and adolescents with cystic fibrosis using observational data from the Cystic Fibrosis Foundation Patient Registry. Methods: The rate of decline in FEV₁ % predicted over 2-7 years among patients age 6-17 years with FEV₁ > 60% predicted who were treated with ibuprofen (1,365) was compared to patients of similar age and disease severity who were not treated with this therapy (8,960). Multilevel repeated-measures mixed-regression models were used to estimate rates of decline, adjusting for characteristics and therapies that influenced FEV₁ decline. Adverse effects were compared among those treated versus not-treated with ibuprofen. Measurements and Main Results: FEV₁ declined less rapidly among patients treated with ibuprofen (difference =0.60% predicted per year; 95% CI 0.31 to 0.89, p<0.0001); a 29% reduction in slope based on an average decline of 2.08 % predicted per year for patients not treated. Those treated with ibuprofen were more likely to have an episode of gastrointestinal bleeding requiring hospitalization, but the occurrence was rare in both groups (annual incidence 0.37% vs. 0.14%; relative risk 2.72, p<0.001). Conclusions: Slower rates of FEV₁ decline are seen in children and adolescents with cystic fibrosis who are treated with ibuprofen. The apparent benefits of ibuprofen therapy outweigh the small risk of gastrointestinal bleeding.