COPD is the fifth leading cause of death in the United States, and acute respiratory infections account for a significant proportion of all primary care visits. Approximately one half of all exacerbations of COPD can be attributed to bacterial infection, and antibiotic therapy has been demonstrated to improve clinical outcomes and hasten clinical and physiologic recovery. The major pathogen continues to be Haemophilus influenzae, and resistance to β-lactam antibiotics such as ampicillin can be expected in 20 to 40% of isolated strains. Certain high-risk patients, in whom the cost of clinical treatment failure is high, can be identified by simple clinical criteria. Patients with significant cardiopulmonary comorbidity, frequent purulent exacerbations of COPD, advanced age, generalized debility, malnutrition, chronic corticosteroid administration, long duration of COPD, and severe underlying lung function tend to fail therapy with older drugs, such as ampicillin, and early relapse can be expected. Treatment directed toward resistant pathogens with potent bactericidal drugs may be expected to lead to improved clinical outcomes and overall lower costs, particularly if hospital admissions and respiratory failure can be prevented. Future studies examining the role of antibiotics should enroll these high-risk patients to determine if new therapies have significant clinical, quality-of-life, and economic advantages over older agents.