Background: Following mild traumatic brain injury (mTBI), also termed concussion, 15-30% of children experience symptoms lasting four weeks or more that reduce their quality of life. Conventional clinical neuroimaging is insensitive to mTBI; however, given the possibility of a neuroinflammatory response following concussion, there is potential for an MRI sequence called quantitative susceptibility mapping (QSM) as a biomarker for injury. In the largest cohort to date, we compared QSM in pediatric concussion patients versus a comparison group of children with orthopedic injuries (OI) and assessed QSM’s performance relative to the current clinical benchmark (5P risk score) for predicting persistent post-concussion symptoms (PPCS). Methods: Children (N=967) aged 8-16.99 years with mTBI or OI were recruited from 5 Canadian pediatric emergency departments. Participants completed QSM at a post-acute assessment (2-33 days post-injury). QSM z-score metrics of susceptibility within 9 regions of interest (ROI) were derived from 371 children (mTBI=255, OI=116). PPCS at 1-month post-injury was defined using reliable change methods. Results: Multivariable linear regression analyses did not reveal a statistically significant difference in susceptibility between mTBI and OI children in any ROI. Multivariable logistic regression analyses revealed increased frontal WM susceptibility was significantly associated with predicting parent-rated reliable change in persistent concussion cognitive symptoms (p=0.001). Frontal WM susceptibility also was nominally significant in a model with all nine regions included (p=0.013). The model with frontal WM and the 5P risk score performed better at predicting parent-rated reliable change in cognitive symptoms than the model with the 5P risk score alone (p=0.002). The area under the curve (AUC) was 0.71(95%CI: 0.62-0.80) for frontal WM susceptibility, 0.67(95%CI: 0.56-0.78) for the 5P risk score, and 0.73(95%CI: 0.64-0.82) for both. Conclusion: We believe this may be the first study to demonstrate a potential imaging biomarker that predicts persistent symptoms using reliable change in children with concussion compared to the current clinical benchmark. Our findings not only suggest a potential neuropathological substrate associated with persistent symptoms, but also highlights the potential for using neuroimaging to assist in the clinical management of concussion in children.