Purpose: To quantify HRQOL of TGN patients using the PedsQL 4.0 generic core scales, and to compare reported HRQOL of TGN adolescents with published data from comparison populations. Methods: Transgender children and adolescents (N = 142; 68% natal females) ages 6–23 years (M = 15.9, SD = 3.7) attending an outpatient clinic for TGN care at an academic pediatric hospital and caregivers of children and adolescents (N = 95) completed the PedsQL 4.0 generic core scales. Scores were compared with published scores for healthy adolescents and adolescents with 10 chronic diseases. Results: TGN youth reported significantly lower overall HRQOL (more than twice the clinically meaningful difference) compared to youth without chronic disease. Total self-reported TGN HRQOL (M(SD), 65.72(17.40)) was lower than all chronic disease comparison groups except for rheumatology and cerebral palsy. TGN youth reported physical functioning (M(SD), 75.33(22.87)) lower than or similar to chronically ill comparisons, but higher than rheumatology and cerebral palsy groups. Psychosocial functioning (M(SD), 59.87(17.83)) was lower than all comparison samples and similar to youth with cerebral palsy. Results were similar for parent proxy-reports of TGN youth HRQOL (LS means: 68.75; 95% CI 65.87–71.61 vs 66.16; 95% CI 62.87–69.45; p = 0.12). Conclusions: TGN youth reported low HRQOL across all domains; most were significantly lower than healthy peers or peers with chronic diseases. Clinicians should understand the magnitude of TGN youth’s low HRQOL and offer them and their caregivers resources to maximize their ability to achieve their full potential for healthy and productive lives.