Background Inhaled glucocorticoids (iGC) have become important first line agents in the management of moderate-to-severe asthma. Severe asthma is associated with reduced glucocorticoid receptor (GCR) binding affinity. Methods To evaluate the potential impact of inhaled fluticasone propionate on markers of airway inflammation [GCR bindig affinity (K d) and eosinophil cationic protein (ECP)] and oral GC requirements in steroid-dependent asthmatics, we examined the effects of fluticasone propionate (FP) 500 micrograms or 1000 micrograms BID and placebo in a double-blind, randomized study of 13 steroid-dependent asthmatics at a single center. Glucocorticoid receptor binding affinity and ECP values were obtained at baseline, 4, 6, 26, and 52 weeks after patients were enrolled into the study. Oral GC dose and FEV 1 values were also recorded at each visit. Results Inhaled FP resulted in large reductions in oral GC requirement by 6 weeks of therapy while no reduction was seen in the placebo group. All patients in the FP 2000 microgram/d group who continued double-blind therapy at 52 weeks were able to eliminate oral prednisone use. In contrast, every patient in the placebo group had to be withdrawn from the study due to poor asthma control. Associated with the oral GC dose reduction on high dose FP therapy, were improvements in GCR binding affinity with the GCR K d falling from 42.5 nM at baseline to 19.5 nM at 6 weeks ( P = .08). The GCR K d values remained stable thereafter with values of 23.5nM at 26 weeks ( P = .02) and 19.5 nM at 52 weeks ( P = .01). In addition, high dose FP therapy resulted in reductions in serum ECP values. Conclusion This study suggests that high dose FP therapy results in significant GC sparing effects associated with improved GCR binding affinity and reductions in serum ECP levels in patients with steroid-sparing asthma.