OBJECTIVES: To prospectively evaluate the long-term societal economic and humanistic benefits of acute treatment of AECB with gemifloxacin compared with clarithromycin. METHODS: Patients with AECB were randomized to receive acute, double-blind, double-dummy treatment with either gemifloxacin 320 mg o.d. for 5 days or clarithromycin 500 mg b.d. for 7 days. Patients in US (n = 386) and Canadian centers (n = 52) were followed for 26 weeks from treatment initiation and the following assessments were made: AECB recurrence requiring antibiotic treatment; respiratory tract infection-related: health care resource utilization, time off and performance at work and usual activities; and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ). RESULTS: In full sample analysis, significantly more patients who received gemifloxacin remained recurrence free after 26 weeks (73.8%[158/214] vs. 63.8%[143/224]; p = 0.024) and were hospitalized less (2.34%[5/214] vs. 6.25%[14/224]; p = 0.059). Cost-effectiveness analysis indicated average direct and indirect cost savings of $329 per patient for gemifloxacin vs. clarithromycin. Ninety-five percent confidence intervals for bootstrapped incremental cost-effectiveness ratios ranged from a cost saving of $14,175 to a cost of $8,888 per recurrence-free patient considering all costs. There was an 82.5% probability of gemifloxacin being both cost saving and more effective than clarithromycin from the societal perspective. A greater improvement in total weighted SGRQ score (lower scores being better), adjusted for baseline, was observed for gemifloxacin vs. clarithromycin at 4, 12 and 26 weeks after initiation of acute treatment (43.3 vs. 44.6 [p = 0.38], 39.4 vs. 41.8 [p = 0.20] and 37.7 vs. 41.0 [p = 0.09], respectively). There was significantly less impact on performance at work (p = 0.01) and usual activities (p = 0.03) at 26 weeks, due to bronchitis, among patients who received gemifloxacin. CONCLUSIONS: Gemifloxacin was very cost-effective from the societal perspective and improved long-term patient outcomes compared with clarithromycin for the treatment of AECB.