INTRODUCTION: In budesonide/formoterol (Symbicort(R) Turbuhaler(R), AstraZeneca, Lund, Sweden) maintenance and reliever therapy (SMART), patients with asthma take a daily maintenance dose of budesonide/formoterol, with the option of taking additional doses for symptom relief instead of a short-acting beta(2)-agonist (SABA). This study assesses the cost-effectiveness of SMART compared with usual care in patients with mild-to-moderate persistent asthma treated by general practitioners in the Netherlands from a societal perspective. METHODS: The study was linked to a randomized, active-controlled, open-label, multicenter, 12-month clinical trial, with a prospective collection of resource use. One hundred and two patients >/=18 years with mild-to-moderate persistent asthma and daily inhaled corticosteroids (ICS) prior to the trial were included. SMART was given as two inhalations of budesonide/formoterol (100/6 mug) once daily, plus additional doses as needed. The control group was treated according to guidelines, which prescribe medium daily doses of ICS plus an SABA if needed. A long-acting beta(2)-agonist (LABA) is added if necessary. Effectiveness was measured as the proportion of asthma-control days, Asthma Control Questionnaire (ACQ) scores, the net proportion of patients with relevant ACQ improvement, and the proportion of well-controlled patients. Costs included asthma medication, physician contacts, and absence from work. RESULTS: Mean total costs for SMART were 134.81 lower (95% CI: -439.48; 44.85). Production losses were 94.10 (95% CI: -300.60; 0.29) lower for SMART (10.77 vs. 104.87). No significant differences in health outcomes were seen, with 3.81 fewer asthma-control days per patient-year for SMART (95% CI: -36.8; 30.8), a 0.049 better ACQ score (95% CI: -0.21; 0.29), a 5.8% larger net proportion of improved patients (95% CI: t15.6%; 27.3%), and a 2.1% (95% CI: -25.5; 20.8%) smaller increase in the proportion of well-controlled patients. CONCLUSIONS: Treating primary care patients with mild-to-moderate persistent asthma with SMART instead of ICS plus bronchodilators does not affect health outcomes and does not increase costs; therefore, is likely to be an alternative for guideline-directed treatment, from a health and economic perspective.