Background: The MOSAIC study compared the effectiveness of moxifloxacin to a basket of 3 standard antibiotic regimens in 730 patients with Anthonisen 1 acute exacerbations of chronic bronchitis (AECB). The clinical outcomes were assessed 7-10 days after study treatment, and then every month until a new AECB or up to 9 months. The study showed superiority of moxifloxacin on clinical cure (return to pre-AECB status) and equivalence to the comparator arm on clinical success (cure or improvement). The long-term benefit of moxifloxacin (composite endpoint) was statistically significant up to 5 months but not at 9 months. METHODS: Using the study data set, exploratory post-hoc logistic regression analyses were performed to identify prognostic factors of short and long term clinical outcomes, and their potential role in confounding the results of the trial. RESULTS: Clinical cure was positively influenced by treatment with moxifloxacin (OR=1.485) at all levels of the identified risk factors, i.e. cardiopulmonary disease (OR=0.58), FEV1 (OR=0.48) and number of previous AECB (OR=0.68). For clinical success, the treatment with moxifloxacin was significantly superior to comparator (OR=1.57) when adjusted on identified risk factors, i.e. cardio-pulmonary disease (OR=0.41) and use of acute bronchodilatators (OR=0.50). The long-term outcome was positively affected by moxifloxacin treatment up to 9 months (HR=0.82)once adjusted on age (HR=1.22), FEV1 (HR=1.27), number of previous AECB (HR=1.63), and acute bronchodilator use (HR=1.48). CONCLUSION: This post-hoc analysis indicates that even in a double-blinded, a priori stratified trial conducted in a clinically homogeneous population, between-group differences could still be confounded by underlying prognosis factors, leading to an underestimation of the treatment impact. Future outcome trials and observational studies in chronic bronchitis should take the identified risk factors into account, either by using a stratified randomisation scheme or by adjusting the statistical analysis plan in a pre-specified manner.