COPD is a leading cause of morbidity and mortality worldwide and is now the third leading cause of death in the United States. Acute exacerbations of COPD (AECOPDs) are common events that often lead to hospitalization, and their frequency worsens with disease progression. AECOPDs are associated with worsened quality of life, increased health-care costs, and increased mortality. Accordingly, there is great interest in preventing AECOPDs to improve outcomes. Both pharmacologic and nonpharmacologic interventions alter the frequency of AECOPDs and COPD-related hospitalizations. To examine the best available evidence, we restricted this review to include studies that used randomized controlled designs lasting at least 6 months. Pharmacologic interventions discussed include inhaled corticosteroids, long-acting β-agonists, long-acting antimuscarinic agents, macrolide antibiotics, and phosphodiesterase-4 inhibitors. The nonpharmacologic interventions discussed include lung volume reduction surgery, pulmonary rehabilitation, and disease management programs.