BACKGROUND: Patient-reported outcomes (PROs) are increasingly used to evaluate the efficacy of new treatments and the progression of chronic diseases. The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a disease-specific, PRO measure of health-related quality of life (HRQOL). We evaluated associations between changes in health status over time and HRQOL in a national CF database. METHODS: Using the Epidemiologic Study of Cystic Fibrosis (ESCF) data, we identified participants who had completed age-appropriate CFQ-R assessments on two occasions separated by 9-15 months. Next, we developed multivariate regression models to test whether associations existed between (1) changes in respiratory signs/symptoms and changes in the respiratory health domains of the CFQ-R, (2) changes in nutritional health status and changes in the nutritional health domains of the CFQ-R, and (3) changes in treatment complexity and changes in the Treatment Burden scale of the CFQ-R. RESULTS: We analyzed 1,947 pairs of assessments: 337 child (mean age 8.9, range 6-13 years), 581 parent (mean age of child 8.8, range 6-13 years), 398 adolescent (mean age 15.3, range 14-17 years), and 631 adult (mean age 26.9, range 18-73 years). On average, we found little change in both health status indicators and CFQ-R domain scores over 1 year. Significant associations over time, however, were found between increases in respiratory symptoms and worse CFQ-R Respiratory Symptom scores, declining weight and worsening scores on CFQ-R nutritional health domains, and increases in treatment complexity and worsening CFQ-R Treatment Burden scores for parent respondents. CONCLUSION: Health status and HRQOL changes were small over a 1-year period in this CF population. However, changes in respiratory symptoms and weight were associated with significant changes on relevant CFQ-R scores, indicating that this PRO is sensitive to changes in health status over time.