Despite the advances in therapy, chronic obstructive pulmonary disease (COPD) requires frequent hospital admissions due to acute exacerbations. We carried out a prospective randomized study of two groups of patients with COPD, one (n = 54) treated with azithromycin (500 mg/day) for three days every 21 days during the winter months, and a control group (n = 40) without treatment. A statistically significant reduction in the number of acute infectious episodes (187) and hospital admissions (22) was observed in the treated group versus the control group (249 and 45, respectively). A short prophylactic treatment course with azithromycin is a good alternative in the management of patients with severe, advanced COPD, and could lead to an improvement in social and healthcare costs