OBJECTIVES:   To evaluate associations between changes in health status over time and health-related quality of life (HRQOL) using the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a disease-specific patient-reported outcome (PRO) measure of HRQOL. METHODS: Using the Epidemiologic Study of Cystic Fibrosis (ESCF) data, we identified participants who had completed age-appropriate CFQ-R assessments on 2 occasions separated by 9 to 15 months.  We developed multivariable 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 1947 pairs of assessments: 337 child (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 with declining weight and worsening scores on the CFQ-R nutritional health domains, and increases in treatment complexity and worsening CFQ-R Treatment Burden scores for parent respondents. CONCLUSIONS: Health status and HRQOL changes were small over a 1-year period in this CF population.  Changes in respiratory symptoms and weight, however, were associated with significant changes on relevant CFQ-R scores, indicating that this PRO is sensitive to changes in health status over time.