Infection is usually considered the main cause of acute exacerbation in chronic obstructive pulmonary disease (COPD). However, uncertainty persists concerning the exact role of bacterial and viral infection in this setting because of the confusing and conflicting data on the role of tracheobronchial microflora and the usefulness of antibiotics in treating this disease. Most COPD patients have evidence of lower respiratory tract chronic bacterial colonization during remission periods as well as during acute exacerbations. This is evidenced by using microbiological analysis of secretions, which reflect all the respiratory tract (sputum), the lower respiratory tract (transtracheal aspiration), or the distal respiratory tract (protected specimen brush). Potentially pathogenic organisms can be recovered from the respiratory tract secretions of virtually all patients with COPD at some time during the course of their disease. Absence of difference in isolation of potentially pathogenic organisms between remission periods and acute exacerbations suggests that bacterial infection is probably not the predominant cause of acute exacerbations in COPD. In contrast, data indicate that the association between viral infections and acute exacerbations is clearer than that with bacteria, affecting probably more than 20% of cases. The role of antibiotic therapy in acute exacerbations of COPD remains controversial. (1) Clearly, antibiotic therapy is urgently required in COPD patients with pneumonia. (2) Review of the conflicting results of studies evaluating the role of antibiotic therapy for preventing acute exacerbations suggests that there is no clear-cut rationale for prophylactic treatment of infection for all patients with COPD; it seems, however, that such treatment may be of some use in highly selected patients, such as those with many exacerbations in the winter. (3) Similarly, data are conflicting concerning the curative use of antibiotic therapy, with some studies suggesting acceleration of recovery, prevention of acute deterioration, and longer period of freedom from recurrent exacerbations; conversely many patients recover from exacerbations without resorting to an antibiotic. Unfortunately, no clear data identify patients who could benefit from antibiotic treatment, probably justifying most clinicians' choice to treat acute exacerbations as infectious events.