The objective of this study was to determine whether the therapeutic benefits of inhaled fluticasone propionate are mediated through topical or systemic effects. Two hundred seventy-four patients with asthma receiving beclomethasone dipropionate or triamcinolone acetonide during a 2-wk, single-blind, run-in period were randomized to inhaled fluticasone propionate powder 100 or 500 micrograms twice daily, oral fluticasone propionate 20 mg once daily, or placebo during a 6-wk treatment period. Patients receiving inhaled fluticasone propionate had a significantly greater probability of remaining in the study over time compared with patients receiving oral fluticasone propionate or placebo (p = 0.001). FEV1 and PEF rates at end point were significantly higher with inhaled fluticasone propionate treatment regimens than with oral fluticasone propionate (with the exception of PEF rates for inhaled fluticasone propionate 100 micrograms) or placebo treatments (p < or = 0.004). Systemic exposure to fluticasone propionate as assessed by trough plasma concentrations and/or 12-hr plasma concentration area under the curve analyses (AUC12) was higher with the oral fluticasone propionate than with the two inhaled fluticasone propionate treatment groups. The results of this study suggest that the therapeutic benefits of inhaled fluticasone propionate are mediated through topical effects in the lungs and not through systemic effects.