Using clinical and claims records from the National Emphysema Treatment Trial, we sought to identify factors that accurately predicted COPD exacerbations. This prospective cohort study consisted of subjects with severe emphysema randomized to medical therapy. Exacerbations were defined as a hospitalization or emergency department visit for COPD. Patient characteristics obtained before randomization were entered as independent variables in multivariable logistic regression models to estimate the risk of exacerbation. Discrimination was determined using the area under the receiver operator characteristic curve (AUC). Baseline measures included demographics, body mass index, pulmonary function, arterial blood gases, radiology studies, dyspnea (Shortness of Breath Questionnaire - SOBQ), health-related quality of life (St. George's Respiratory Questionnaire - SGRQ), 6-minute walk, exercise capacity, medication use, prior exacerbations and co-morbidity. In 610 participants, 26.6% had a COPD exacerbation over 1-year follow-up. In a model incorporating spirometry, PaO2, dyspnea, prior exacerbations and co-morbidity, a 5-point decrement in percent predicted FEV1 (OR 1.16, 95% CI 1.00-1.34) and a 5-point worsening in SOBQ (OR 1.08, 1.02-1.14) independently predicted exacerbations (AUC for full model 0.68). Combining physiologic variables, dyspnea, prior exacerbations and co-morbidity may be useful in identifying patients at high risk for COPD exacerbations.