The number of senile patients with chronic obstructive pulmonary disease (COPD) has recently increased due to an increase in life expectancy, the habit of smoking and the inhalation of toxic particles. COPD exacerbations are caused by airway bacterial and viral infections, as well as the inhalation of oxidative substrates. COPD exacerbations are associated with the worsening of symptoms and quality of life, as well as an increased mortality rate. Several drugs, including long-acting anti-cholinergic agents, long-acting β(2)-agonists and inhaled corticosteroids, have been developed to improve symptoms in COPD patients and to prevent COPD exacerbations. Treatment with macrolide antibiotics has been reported to prevent COPD exacerbations and improve patient quality of life and symptoms, especially in those patients who have frequent exacerbations. In addition to their antimicrobial effects, macrolides have a variety of physiological functions, such as anti-inflammatory and anti-viral effects, reduced sputum production, the inhibition of biofilm formation and the inhibition of bacterial virulence factor production. These unique activities may relate to the prevention of exacerbations in COPD patients who receive macrolides. Herein, we review the inhibitory effects that macrolides have on COPD exacerbations and explore the possible mechanisms of these effects.