Chronic bronchitis is common among adults and infectious exacerbations contribute considerably to morbidity and mortality. We aimed to compare the safety and efficacy of moxifloxacin to azithromycin for the treatment of patients with acute exacerbations of chronic bronchitis (AECB) of suspected bacterial origin. Between October 1998 and April 1999, 567 patients with AECB were enrolled at 37 centers across the United States and Canada of which 280 (49%) had acute bacterial exacerbation of chronic bronchitis (i.e. pretherapy pathogen). Patients were randomized to either oral moxifloxacin 400 mg administered once daily for 5 days or azithromycin for 5 days (500 mg qd x 1, then 250 mg qd x 4). For the purpose of study blinding, all patients received encapsulated tablets. The main outcome measure was clinical response at the test-of-cure visit (14-21 days post-therapy). Secondary measures included bacteriologic response and a time-course of bacteriological eradication (one center only). Three patient populations were analysed for efficacy: clinically-valid, microbiologically-valid (i.e. those with a pretherapy pathogen), and intent-to-treat (i.e. received at least one dose of study drug). For the efficacy-valid group, clinical response at the test-of-cure visit was 88% for patients in each treatment group. In 237 microbiologically-valid patients, corresponding clinical resolution rates were 88% for 5-day moxifloxacin vs. 86% for 5-day azithromycin. Bacteriological eradication rates at the end of therapy were 95% for 5-day moxifloxacin and 94% for the azithromycin group. Corresponding eradication rates at the test-of-cure visit were 89% and 86%, respectively. Of note, eradication rates at test-of-cure for Haem. philos influenzae and H. parainfluenzae for moxifloxacin were 97% and 88% compared to 83% and 62% respectively for azithromycin. Among 567 intent-to-treat patients (283 moxifloxacin and 284 azithromycin), drug-related events were reported for 22% and 17%, respectively. Diarrhea and nausea were the most common drug-related events reported in each treatment group. Moxifloxacin 400 mg once daily for 5 days was found to be clinically and bacteriologically equivalent to 5-day azithromycin for the treatment of AECB of proven bacterial etiology. Given its excellent in-vitro activity, especially against antibiotic-resistant respiratory pathogens, and its acceptable safety profile, moxifloxacin should be considered an effective alternative therapy for patients with AECB of suspected bacterial origin.