Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.