Aims Inhaled corticosteroids alone or in combination with long acting b 2 -agonists are indicated for use in mild persistent asthmatics. We set out to evaluate effects on airway hyperresponsiveness (AHR) and airway calibre using hydrofluoroalkane fluticasone/salmeterol (FP/SM) vs. double the dose of fluticasone alone (FP). Methods Fourteen mild persistent asthmatics completed a randomized double-blind crossover study with 1-week run-in and washout periods prior to treatments. Subjects received 3 weeks of FP 250 m g or FP 125 m g/SM 25 m g as 1 puff twice daily. Methacholine PD 20 and lung function were measured after both baseline and treatment periods. Results There were no significant differences in baseline values prior to randomized treatments. Compared with pooled baseline, FP/SM and FP conferred improvements (P < 0.05) on methacholine PD 20 : 2.5 (95% confidence interval 1.7, 3.2) and 1.6 (0.8-2.3) doubling dose improvements, respectively; between FP/SM vs. FP there was a 0.9 (0.4, 1.4) doubling dose difference (P < 0.05). For forced expiratory volume in 1 s (FEV 1 ), forced mid-expiratory flow (FEF 25 -75 ) and morning peak expiratory flow (PEF), FP/SM but not FP conferred improvements (P < 0.05) compared with pooled baseline, with FP/SM being greater than FP (P < 0.05): differences in FEV 1 of 7.2% (3.8, 10.6) predicted, FEF 25 -75 of 11.2% (6.3, 16.1) predicted, and morning PEF of 17 L min -1 (1-32). Conclusions FP/SM conferred improvements on AHR and airway calibre, while twice the dose of FP improved only AHR in patients with mild asthma. The differential effects of FP/SM and FP suggest separate but complementary actions of the two moieties on airway inflammation and smooth muscle stabilization. This may explain the beneficial effects of combination inhalers on exacerbations.