This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double‐dummy, double‐blind, placebo‐controlled 3‐period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. Ata 2‐week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3‐hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean 95% confidence interval) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti‐inflammatory compounds in early development.