Background Once-daily dosing with an effective inhaled corticosteroid (ICS) would likely enhance compliance and, therefore, aid in the management of asthma. Objective Several once-daily dosing regimens of mometasone furoate (MF) administered by dry powder inhaler (DPI) were compared with a twice-daily dosing regimen in 286 patients with mild to moderate persistent asthma who were previously being treated with ICS. Methods During a 2-week open-label phase, patients received MF-DPI, 200 μg twice daily. They were then randomized to continue MF-DPI, 200 μg twice-daily treatment or to receive MF-DPI, 200 μg once daily in the morning (am), 200 μg once daily in the evening (pm), 400 μg once daily am, or placebo as part of the 12-week, double-blind phase. The primary efficacy variable was the mean change from the baseline to endpoint (last evaluable observation) for FEV 1 . Results Once-daily MF-DPI, 400 μg, am maintained FEV 1 , and morning peak expiratory flow rate, FVC, FEF 25%-75% , and asthma symptom scores, at levels similar to those for MF-DPI, 200 μg twice daily and significantly better than placebo. Once-daily MF-DPI, 200 μg,pm was effective in maintaining pulmonary function, but was less effective on other efficacy measures. In comparison to the other MF-DPI groups, once-daily MF-DPI, 200 μg, am was not as effective overall. The incidence of local adverse events, including oral candidiasis, was low with all dosages. Conclusions Once-daily MF-DPI, 400 μg, am was as effective as MF-DPI, 200 μg twice daily, whereas once-daily MF-DPI, 200 μg, was more effective when administered in the evening compared with morning, for patients receiving ICS therapy. Once-daily dosing offers an effective and convenient treatment that could aid compliance in the treatment of asthma.