Background: Modern H₁-antihistamines differ in their in vitro binding affinity, but their comparative in vivo bioactivity in asthmatic airways is unknown. Objectives: We compared clinically recommended doses of 3 H₁-antihistamines on airway hyperresponsiveness to AMP challenge (the primary outcome variable). Methods: Sixteen atopic patients with mild-to-moderate asthma of whom 10 were receiving inhaled corticosteroid therapy (all had positive results to house dust mite on skin prick testing) were randomized in a double-blind, placebo-controlled, cross-over fashion to receive single doses of 5 mg of desloratadine, 180 mg of fexofenadine hydrochloride (FEX), 5 mg of levocetirizine dihydrochloride (LEV), or placebo, with AMP challenge performed 12 hours after dosing. Results: All H₁-antihistamines demonstrated significantly greater (P < .05) geometric mean ± SEM AMP PC₂₀ values compared with that of placebo (86 ± 29 mg/mL): desloratadine, 189 ± 54 mg/mL; FEX, 176 ± 57 mg/mL; and LEV, 163 ± 48 mg/mL. Prechallenge forced expiratory flow at 25% to 75% of maximal lung volume (percent predicted) but not FEV₁ was significantly higher (P < .05) for all H₁-antihistamines compared with that of placebo (53% ± 4%): desloratadine, 62% ± 4%; FEX, 62% ± 4%; and LEV, 59% ± 3%. There were no significant differences in either AMP PC₂₀ or lung function values among the H₁-antihistamines. Conclusion: Single doses of H₁-antihistamines improved airway hyperresponsiveness and small-airways caliber to a similar degree. Data for in vitro binding affinity do not therefore translate into commensurate differences in in vivo bioactivity at clinically recommended doses. (J Allergy Clin Immunol 2003;111:337-41.)