Purpose <p>Self-reported quality of life (QOL) is an important outcome in clinical research, including psychotherapy and pharmacotherapy studies. The Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQLESQ) has been widely used as a summed total score to assess QOL outcomes in clinical trials. Despite widespread use, the PQLESQ has only been validated in youth seeking outpatient treatment of depression or obsessive-compulsive disorder (OCD), and a general population sample ages 11–18. The aim of the present study is to evaluate the unidimensional fit and measurement invariance (MI) of the PQLESQ across numerous subgroups of a sample of youth treated at a private, not-for-profit psychiatric hospital system in the United States (<i>N</i> = 14740).</p> Methods <p>Confirmatory factor analysis (CFA) was used to evaluate goodness of fit. MI was evaluated using multigroup CFA (MCFA) to test configural, metric, and scalar invariance. Comparisons were between (1) boys and girls, (2) White, Black, Asian, and multiracial youth, (3) Hispanic and Non-Hispanic youth, (4) youth being treated at each level of care (intensive outpatient, partial hospitalization, residential, and inpatient care), and (5) youth being treated for eating disorders, OCD and anxiety, depression, emotion dysregulation, substance use disorders, and multiple diagnoses.</p> Results <p>The unidimensional fit of the 14-item PQLESQ was adequate, although goodness of fit measures fell below commonly cited thresholds. MCFA supported scalar invariance across all subgroups compared.</p> Conclusion <p>Findings support MI of the 14-item unidimensional PQLESQ across subpopulations of youth seeking intensive psychiatric healthcare.</p> Plain english summary <p>In addition to relieving symptoms, medical and mental healthcare aim to improve patient’s quality and enjoyment of life. The Pediatric Quality of Life and Enjoyment Scale (PQLESQ) is a popular measure of QOL for youth self-report. The study confirmed that members of six subpopulations of youth seeking psychiatric treatment respond to the PQLESQ on the same scale, allowing for meaningful raw score comparisons: boys and girls, White, Black, Asian, and mixed race youth, Hispanic and non-Hispanic youth, youth presenting to inpatient, residential partial hospitalization, or intensive outpatient treatment, and youth presenting to treatment programs aimed at treating depression, obsessive compulsive and anxiety disorders, eating disorders, mood disorders with significant emotion dysregulation, mood disorders with multiple mental health comorbidities, and mental health disorders with comorbid substance use disorders. Based on the results of this study, there is support for using the PQLESQ in youth admitted to intensive mental healthcare treatment and comparing the raw scores of youth from all subpopulations in the study.</p>