Inhaled corticosteroids are now first-line therapy for most patients with asthma. However, it has been shown that there is ongoing airway inflammation and airway hyperresponsiveness even in the presence of low dose inhaled corticosteroids. To ensure a maximal therapeutic potential we investigated the effect of 3 mo of a very high dose of a new inhaled corticosteroid, fluticasone propionate (FP) (equivalent to 4,000 micrograms daily of beclomethasone dipropionate [BDP]. Twenty asthmatics with mild-to-moderate disease were recruited into this single-blind study. Baseline data were compared with those from 26 normal subjects. Differences in inflammatory indices between asthmatics and normal subjects were detected in both BAL and endobronchial biopsies. After the FP treatment period there was a significant improvement in symptom scores, lung function, and airway responsiveness by a mean 2.8 doubling dilutions of methacholine. Reduction in the airway lymphocyte load and lymphocyte activation was demonstrated and is likely to be an important mechanism mediating the effects of inhaled corticosteroids. Decreased mast cell numbers and activity in atopic asthma suggest that corticosteroids may have additional targets in different types of asthma. Reduced lymphocyte and mast cell activity was found with high dose FP even in those receiving low dose maintenance BDP prior to the study, suggesting a dose-response effect of inhaled corticosteroids on airway inflammation. BAL eosinophilia was still present after FP, indicative of a component of asthmatic airway inflammation that is relatively resistant to corticosteroid therapy.