Objective: To study the effectiveness and safety of budesonide/formoterol (Symbicort®) Maintenance And Reliever Therapy (Symbicort SMART®, AstraZeneca, Södertalje, Sweden), a simplified management approach with one inhaler compared with conventional best practice (CBP) with multiple inhalers in patients with persistent asthma. Design: Open-label randomised controlled parallel group trial, 6-month treatment. Participants: A total of 908 patients ≥ 12 years of age, with persistent asthma receiving treatment with inhaled corticosteroids (ICS), either alone or in conjunction with long-acting β2-agonist. Main outcome measures: Time to first severe asthma exacerbation and number of severe asthma exacerbations. Results: No difference between groups was seen in time to first severe exacerbation (p = 0.75). Exacerbation rates were low in both groups. A total of 12 patients in the Symbicort SMART® group experienced a total of 14 severe asthma exacerbations, and 19 patients in the CBP group experienced a total of 25 severe asthma exacerbations (annual rate 0.07 vs. 0.13 p = 0.09). The mean daily dose of ICS expressed in BDP equivalent was significantly lower in the Symbicort SMART® group (including as-needed use) vs. in the CBP group (749 μg vs. 1059 μg; p < 0.0001). Mean scores in Asthma Control Questionnaire, 5 question version improved significantly in the SMART group compared with the CBP group (p = 0.0026). Symbicort SMART and CBP were equally well tolerated. The mean drug cost/patient/month was significantly lower for the patients in the Symbicort SMART group compared with patients receiving CBP (51.3 € vs. 66.5 €; p < 0.0001). Conclusions: In Belgian patients, a simplified regimen using budesonide/formoterol maintenance and reliever therapy was at least as effective at improving clinical control compared with CBP with a significantly lower ICS dose and significantly lower drug costs.