Rationale: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. Objective: We tested the safety, tolerability, pharmacological and biological efficacy of a tachykinin NK₁/NK₂ receptor antagonist, AVE5883, in asthmatics in 2 double-blind, placebo-controlled, cross-over studies. Methods: The pharmacological efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 asthmatics. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple dose trial (4.8 mg TID, 9 days) in 12 asthmatics with dual responses to inhaled house dust mite. On day 8, an allergen challenge was conducted and airway response was measured by FEV₁ until 9 h post-allergen. Exhaled NO, PC₂₀FEV₁(Methacholine) and induced sputum were performed on days 1,7 and 9. Results: AVE5883 had a bad taste and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose-response to NKA by 1.2 doubling doses. Unexpectedly, pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. However, there were no significant differences in the allergen-induced changes in exhaled NO, PC₂₀FEV₁(Methacholine) and sputum cell differentials between placebo and AVE5883. Conclusions: Despite its demonstrated pharmacological activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.