ICD-9-CM diagnosis codes are increasingly used to estimate the burden of disease, as well as to evaluate the quality of care and outcomes of various conditions. Acute exacerbations of COPD (AE-COPD) are common and associated with substantial health and financial burden in the U.S. Whether published algorithms that employ different combinations of ICD-9-CM codes to identify patients hospitalized for AE-COPD yield similar or different estimates of disease burden is unclear. In this study, the Nationwide Inpatient Sample from years 2000-2006 was used to identify and compare the number of hospitalizations, healthcare utilization, and outcomes for patients hospitalized for AE-COPD in the U.S. AE-COPD was identified using five different published ICD-9-CM algorithms. Estimates of the annual number of hospitalizations for AE-COPD in the U.S. varied more than 2-fold (e.g., 421,000 to 870,000 in 2006). Outcomes and healthcare utilization of patients hospitalized for AE-COPD varied substantially, depending on the algorithm used (e.g., in-hospital mortality 2.0% to 5.1%, total hospital days 2.0 to 5.1 million in 2006). Observed trends in the number of hospitalizations over the 7-year period varied depending on which algorithm was used. In conclusion, the estimated health burden and trends in hospitalizations for AE-COPD in the United States differ, depending on which ICD-9-CM algorithm is used. To improve our understanding of the burden of AE-COPD and to ensure that quality of care initiatives are not misdirected, a validated approach to identifying patients hospitalized for AE-COPD is needed.