Asthma guidelines recommend reducing inhaled corticosteroids (ICS) to the minimum effective dose, but the timing of long-acting β₂-agonist (LABA) withdrawal is unclear. Recent FDA guidelines recommend LABA withdrawal once asthma is well-controlled. This 13-month double-blind study of patients taking high-dose combination therapy investigated the effect of discontinuation of LABA before ICS down-titration. Adults using salmeterol/fluticasone combination (SFC) 50/500 μg bd were randomized to SFC 50/500 μg bd or fluticasone propionate (FP) 500 μg bd, with subsequent ICS down-titration 8-weekly using a clinical algorithm. The primary outcome was mean daily FP dose, including ICS for exacerbations. 82 subjects were randomized. Asthma was well-controlled at baseline, with mean FEV1 84.8% predicted and Asthma Control Questionnaire (ACQ) score 0.9. There was no significant difference in mean daily FP dose (SFC: 721 μg, FP:816 μg, p = 0.3), but final dose was lower with SFC (534 μg cf. 724 μg, p = 0.005). ICS dose was reduced by ≥80% in 41% SFC and 15% FP patients. Ambulatory lung function was significantly higher with SFC, but there were no differences between groups in rescue β₂-agonist use, clinic spirometry, airway responsiveness, ACQ, sputum eosinophils or FeNO. Baseline airway responsiveness, and pre-reduction blood eosinophils, were significant predictors of mean daily FP dose and dose reduction failure respectively. Many patients prescribed high-dose combination therapy may be over-treated. Substantial reductions in dose can be achieved with a clinical algorithm, reaching lower FP doses with SFC than FP without losing asthma control or increasing disease activity. This study was commenced before mandatory registration of clinical trials.