Rationale Exacerbations in non-cystic fibrosis (CF) bronchiectasis are associated with worsening lung functions and quality of life. A standardized definition of exacerbation could improve clinical care and research. Objective To formulate a clinically useful definition of pulmonary exacerbation for pediatric non-CF bronchiectasis. Methods A cohort of 69 children with non-CF bronchiectasis was prospectively followed for 900 child-months. The changes in clinical, systemic, and lung function parameters from 81 exacerbations were statistically evaluated using conditional logistic regression, receiver operating characteristic, sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) to formulate a definition of a pulmonary exacerbation. Formation of major and minor criteria was statistically based and models were developed. Measurements and Main Results Wet cough and cough severity (score ¥2) over 72-hr were the best predictors of an exacerbation with area under the curve (AUC) of 0.85 (95% CI 0.79-0.92) and 0.84 (95% CI 0.77-0.91), respectively. Sputum color, chest pain, dyspnea, hemoptysis, and chest signs were significant though minor criteria. Inclusion of serum C-reactive protein, amyloid-A, and IL6 to the definition improved its specificity and PPV. Our final combined model consisted of one major with one investigatory criterion (PPV 91%, NPV 72%); two major criteria (PPV 79%, NPV 91%); or one major and two minor criteria (PPV 79%, NPV 94%). Conclusions Pulmonary exacerbation in children with non-CF bronchiectasis can be validly predicted using a standardized assessment of clinical features, with additional systemic markers improving predictive values. This definition potentially facilitates earlier detection (leading to appropriate management) of exacerbations.