PURPOSE:To understand differences in perceptions of patient-reported outcome domains between children with asthma and children from the general population. We used this information in the development of patient-reported outcome items for the Patient-Reported Outcomes Measurement Information System Pediatrics project. METHODS:We conducted focus groups composed of ethnically, racially, and geographically diverse youth (8-12, 13-17 years) from the general population and youth with asthma. We performed content analysis to identify important themes. RESULTS:We identified five unique and different challenges that may confront youth with asthma as compared to general population youth: (1) They experience more difficulties when participating in physical activities; (2) They may experience anxiety about having an asthma attack at anytime and anywhere; (3) They may experience sleep disturbances and fatigue secondary to their asthma symptoms; (4) Their health condition has a greater effect on their emotional well-being and interpersonal relationships; and (5) Youth with asthma report that asthma often leaves them with insufficient energy to complete their school activities, especially physical activities. CONCLUSIONS:The results confirm unique experiences for children with asthma across a broad range of health domains and enhance the breadth of all domains when creating an item bank.