AIM: The objective of this study was to evaluate the different outcomes associated with the use of budesonide/formoterol compared to fluticasone/salmeterol in fixed combinations in patients with COPD in a "real-world" setting. The outcomes included exacerbation rates and health care costs. PATIENTS AND METHODS: An observational retrospective cohort analysis, based on administrative databases of three local health units, was conducted. Patients with at least one prescription of fixed-dose combination of inhaled corticosteroids and long-acting ß2-agonists (budesonide/formoterol or fluticasone/salmeterol), at dosages and formulations approved for COPD in Italy, between January 1, 2009 and December 31, 2011 (inclusion period), were included. Patients were followed until December 2012, death or end of treatment (follow-up period), whichever occurred first. Patients were included if they were aged ≥40 years and had at least 6 months of follow-up. Propensity score matching was performed to check for confounding effects. Number of hospitalizations for COPD and number of oral corticosteroid and antibiotic prescriptions during follow-up were analyzed using Poisson regression models. The cost analysis was conducted from the perspective of the National Health System. RESULTS: After matching, 4,680 patients were analyzed, of which 50% were males with a mean age of 64±13 years. In the Poisson regression models, the incidence rate ratio for budesonide/formoterol as compared to fluticasone/salmeterol was 0.84 (95% confidence interval [CI]: 0.74-0.96, P=0.010) for number of hospitalizations, 0.89 (95% CI: 0.87-0.92, P<0.001) for number of oral corticosteroid prescriptions and 0.88 (95% CI: 0.86-0.89, P<0.001) for number of antibiotic prescriptions. The mean annual expenditure for COPD management was €2,436 for patients treated with budesonide/formoterol and €2,784 for patients treated with fluticasone/salmeterol. CONCLUSION: Among patients with COPD, treatment with a fixed combination of budesonide/formoterol was associated with fewer exacerbations and a lower, but not significant, cost of illness than the treatment with fluticasone/salmeterol. Real-world analyses are requested to ameliorate interventions to address unmet needs, optimizing treatment pathways to improve COPD-related burden and outcomes.