The efficacies and safeties of a three-dose regimen of azithromycin (500 mg once daily for 3 days) and a 15-dose regimen of amoxicillin (500 mg three times daily for 5 days) were compared in a double-blind manner in patients with an acute exacerbation of chronic bronchitis. Azithromycin is a new azalide antibiotic (12) that differs from erythromycin by a methyl-substituted nitrogen at position 9a within the macrocyclic ring. This modification has resulted in improved stability at low pH and improved potency against Haemophilus influenzae and Moraxella (Branhamella) catarrhalis (10, 12). Although serum levels remain low after oral administration, the levels achieved in sputum, bronchial mucosa, and alveolar macrophages are sustained for 4 days well above the MICs for many respiratory pathogens (4). Moreover, azithromycin proved to be superior to erythromycin in a mouse pneumococcal pneumonia model, probably because of these improved pharmacokinetic parameters (2). Since the drug concentrates in macrophages as well, it is potentially active against intracellular pathogens such as Legionella pneumophila (4, 10). These properties suggested that a very short course (3 days) of treatment with once-daily administration of azithromycin could be useful in the treatment of respiratory infections. This paper reports the results of a double-blind comparison with a 5-day course of amoxicillin in patients with acute exacerbations of chronic bronchitis.