Abstract: A novel microsphere formulation of azithromycin enables administration as a single, 2.0-g oral dose, while maintaining tolerability. This multicenter, randomized, double-blind, double-dummy study compared azithromycin microspheres with levofloxacin (500 mg/d for 7 days) in the treatment of acute exacerbations of chronic bronchitis. Subjects had Anthonisen Type 1 exacerbations, were ≥50 years old, and had a ≥20 pack-year smoking history. The primary end point was clinical response at the test of cure visit (Days 14-21). The secondary end point was bacterial response at the test of cure visit in subjects with a baseline pathogen. Clinical cure rates in the clinical per protocol population were 93.6% (206/220) for azithromycin microspheres and 92.7% (202/218) for levofloxacin. Clinical cure rates in subjects with Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis infection were 95% (19/20), 94.7% (18/19), and 92% (23/25), respectively, for azithromycin microspheres, and 100% (26/26), 90.5% (19/21), and 81.3% (13/16), respectively, for levofloxacin. Both treatments were well tolerated. A single dose of azithromycin microspheres was as effective as a 7-day course of levofloxacin in the treatment of acute exacerbations of chronic bronchitis and was well tolerated.