Measuring health-related quality of life (HRQL) in children with attention-deficit/hyperactivity disorder (ADHD) in clinical trials can complement efficacy measures, offering a complete picture of the impact of disease and treatment on overall well-being. The purpose of the current study was to psychometrically validate a multidimensional, generic HRQL instrument completed by parents of children with ADHD. A total of 921 children and adolescents with ADHD participated in a clinical study of atomoxetine. Subjects' parents completed the 50-item Child Health Questionnaire-Parent Version (CHQ-PF50) at baseline and week 10. ADHD symptoms and behavioral problems were assessed using parent and clinician rating scales. Internal consistency reliability at baseline was 0.88 for the CHQ-PF50 Psychosocial Summary Score, ranging from 0.53 to 0.91 for subscale scores. Construct validity was supported by statistically significant correlations between CHQ-PF50 psychosocial scores and parent and clinician symptom ratings. Several methods were used to determine clinically meaningful differences in patient outcomes: inter- and intra-patient mean CHQ-PF50 change scores were tested and standard error of measurement (SEM) and effect sizes were calculated. Study results indicate the CHQ-PF50 is reliable, valid, and responsive to change in ADHD symptoms, suggesting it may provide a means of assessing HRQL outcomes associated with treatments for ADHD.