OBJECTIVES: To develop a cost-effectiveness analysis of formoterol associated to budesonide for maintenance and reliever therapy (FB SMART) versus salmeterol associated do fluticasone (SF) in the treatment of patients with moderate to severe persistent asthma, under the Brazilian societal perspective. METHODS: A Markov model was developed to project costs and outcomes associated with disease progression of patients with moderate to severe persistent asthma receiving SMART therapy or SF in a one year time horizon.  Weekly cycles were considered and the model structure consisted of four possible health states: disease control, use of oral corticoids (OC), hospitalization/emergency visit (H/ER) and death. The probabilities of having severe exacerbations (OC or H/ER) were extracted from the study by Kuna et al. All cause mortality rates were obtained from national epidemiological databases. Adverse events were not significantly different between comparators so were excluded from the model. Outcomes were expressed as severe exacerbations avoided (SEA) and only direct medical costs were included in the analysis. Resource use during hospitalization was estimated based on an expert panel. Maximum prices to consumer were obtained for drugs, and procedure costs were extracted from the Brazilian Classification of Medical Procedures (CBHPM). RESULTS: In one year, the average number of severe exacerbations was 0.2436 in the SMART group and 0.3928 in the SF group, resulting in 0.1492 severe exacerbations avoided. Total cost for the SMART and SF groups were R$1823.56 and R$1417.49, respectively (incremental cost=R$406.07). The incremental cost-effectiveness ratio in 1 year was R$2721/SEA (US$1944 2005-PPP-index USD1.0=R$1.4). The variables that most influenced the results were the costs of SMART and SF therapy and the cost of hospitalization. CONCLUSIONS: SMART therapy reduces the risk of severe exacerbations when compared to SF in patients with moderate to severe persistent asthma, at a reasonable incremental cost, being a valuable alternative for these patients.