Background Children with severe asthma have persistent symptoms despite treatment with inhaled corticosteroids (ICSs). The differentiating features of severe asthma in children are poorly defined. Objective To identify features of severe versus mild-to-moderate asthma in school-age children using noninvasive assessments of lung function, atopy, and airway inflammation. Methods A total of 75 children (median age, 10 years) with asthma underwent baseline characterization including spirometry and lung volume testing, methacholine bronchoprovocation, allergy evaluation, and offline measurement of exhaled nitric oxide (FENO). Twenty-eight were followed longitudinally over 6 months. Participants were assigned to the severe asthma subgroup if they required high-dose ICS plus 2 or more minor criteria. Results Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of FENO and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV1 and increase in FENO persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%). Conclusion Severe asthma in childhood is characterized by poor symptom control despite high-dose ICS treatment and can be differentiated from mild-to-moderate asthma by measurement of lung function and FENO. Clinical implications Clinicians should suspect severe asthma in children with poor response to ICS, airway obstruction, and high FENO.