Abstract Context Measuring health-related quality of life (HRQoL) is a crucial aspect of evaluating health care outcomes. Patients with congenital adrenal hyperplasia (CAH) often self-report deficiencies in HRQoL. Objective The aim of our study was to develop a disease-specific patient-reported outcome (PRO) instrument to evaluate the HRQoL of patients > 16 years old with classic CAH. Methods Following the FDA guidelines for developing PRO instruments, we developed a conceptual framework for the instrument. A preliminary instrument was created after interviewing a representative sample of 12 patients (aged 16 to 68 years) with CAH and 3 parents and obtaining expert feedback from 4 endocrinologists. The instrument was edited after cognitive interviews with 6 patients. Internal consistency of the instrument was evaluated using Cronbach's alpha. Validity was assessed by comparing the scores of our instrument with scores from widely used validated instruments for HRQoL and PRO not specific to CAH. Results Sixty-nine patients 16 to 75 years old participated in validating our preliminary instrument. The final questionnaire consists of 44 questions within 7 domains: General Health, Adrenal Insufficiency, Glucocorticoid Excess, Physical Functioning, Mental Health and Cognition, Social Functioning, and Sexual Functioning, with acceptable internal consistency (Chronbach's alpha ≥ .6) and validity (r = −0.350 to 0.866). Conclusion CAHQL is the first validated PRO instrument to capture disease-specific HRQoL outcomes in CAH. In addition to its anticipated use in the clinical setting, the instrument could be used to assess the efficacy of novel treatments in development.