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Background: Evaluating adolescent athletes' perceived health status after a sport-related injury can provide important direction for health promotion strategies and preparation for a successful return to play. Furthermore, comparing specific injury types regarding their impact on athletes' perspectives of their global and domain-specific health perceptions allows for a more detailed understanding of an athlete's experience while also providing avenues for targeted treatment strategies., Purpose: To compare health-related quality of life (HRQOL) between high school athletes who had sustained either a concussion or an acute ankle injury and compare how these injury types related to their global and domain-specific HRQOL across recovery., Study Design: Cohort study; Level of evidence, 3., Methods: Electronic medical records created by athletic trainers working in 32 high school facilities were examined, and records from 1749 patients who sustained either a sport-related concussion (n = 862) or ankle sprain (n = 887) were screened for inclusion. HRQOL was assessed by self-reported scores on the Pediatric Quality of Life Inventory (PedsQL) at 2 time points after injury (T 1 = 0-2 days; T 2 = 11-29 days). A 2-way group by time analysis of variance was conducted to examine differences in trajectories and disrupted areas of HRQOL., Results: Overall, 85 patient cases (46 concussion, 39 ankle sprain) fit the inclusion criteria. Each injury group exhibited improved global and domain-specific PedsQL scores between their 2 measured time points ( P < .05), indicating recovery. However, domain-specific comparisons revealed that at T 2 , patients who had sustained an ankle sprain reported significantly lower PedsQL physical functioning scores (78.3 ± 19.3 vs 86.2 ± 15.7 for concussion; P = .005), whereas patients who had sustained a concussion reported lower scores related to their school functioning (80.0 ± 20.0 vs 90.8 ± 12.7 for ankle sprain; P = .006)., Conclusion: The study results indicated that in high school athletes, the trajectories and disrupted areas of HRQOL stemming from a sport-related injury may be influenced differentially when comparing concussions with ankle sprains., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2022.)