Background: Longitudinal data on health-related quality of life (HRQOL) and fatigue in paediatric Duchenne muscular dystrophy (DMD) are limited. Recently, fatigue was reported to be the greatest predictor of poor HRQOL in paediatric DMD. Understanding the trajectory of HRQOL and its relationship with fatigue may facilitate the development of improved therapeutic strategies. Our objective was to describe three-year changes in HRQOL and fatigue in children with DMD. Methods: Patients identified via the Canadian Neuromuscular Disease Registry received mailed questionnaires (2013–2016). HRQOL was assessed using the PedsQLTM GCS and NMM domains, and fatigue was assessed using the MFS domain (patient- and parent-report). Mean three-year change in scores were computed. Pearson correlations were computed between three-year change in HRQOL and fatigue. Results: Mean decline in MFS scores for patient- and parent-reports were 1.03 and 1.19, respectively. Mean decline in GCS scores for patient- and parent-report were 1.75 and 4.13, respectively. Mean change in NMM scores for patient- and parent-report were 0.72 and -8.36, respectively. Change in MFS score was associated with changes in GCS (r=0.72, p<0.001) and NMM scores (r=0.84, p<0.001) by patient-report. Conclusions: Children with DMD experience worse fatigue and HRQOL over time. Parents perceive a greater decline in HRQOL over time compared to patients.