OBJECTIVES: To compare the cost-effectiveness of budesonide/formoterol in a single inhaler used as maintenance and reliever medication (Symbicort SMART) versus clinician directed titration of maintenance fluticasone/salmeterol (Advair) plus as-needed salbutamol in controlling asthma in adults and adolescents. METHODS: An economic evaluation was conducted based on the results of a large (N=2143), open-label, randomized, controlled effectiveness trial in which health resource utilization was prospectively collected. Primary outcome measurements included time to first exacerbation and number of severe exacerbations. Costs included direct medical costs (physician/emergency room visits, hospitalizations, asthma drug costs) and productivity (absenteeism). The time horizon was one-year which corresponded to the duration of the trial. Prices were obtained from 2005 Canadian sources. Both health care (HC) and societal (Soc) perspectives were considered. Deterministic univariate sensitivity analyses were conducted. RESULTS: In the clinical trial, Symbicort was superior to Advair with respect to the number of exacerbations, lung function and use of as-needed rescue. The annualized rate of severe exacerbations was 0.24 in the Symbicort arm and 0.31 in the Advair arm (p=0.0025). From the HC perspective, the mean cost per patient-year was $1315 in the Symbicort arm versus $1541 in the Advair arm. From the Soc perspective, it was $1538 for Symbicort and $1854 for Advair. Symbicort SMART was dominant (more effective, less expensive) in the base case analysis from both the HC and Soc perspectives. The results were robust under sensitivity testing. CONCLUSIONS: The strategy of Symbicort SMART which allows the combination of budesonide/formoterol to be used as both maintenance and reliever medication is dominant over a strategy of clinician directed titration of Advair (fluticasone/salmeterol) therapy.