The cysteinyl leukotrienes are potent proinflammatory mediators that, in addition to their bronchospastic actions, can also contribute to mucociliary dysfunction, a central component of the pathophysiology of asthma. In this study, we determined if montelukast, a cysteinyl leukotriene 1 receptor antagonist, could prevent and/or reverse antigen-induced mucociliary dysfunction in allergic sheep. We measured tracheal mucus velocity, a marker of mucociliary clearance, before and for 8h after antigen challenge in six animals treated with montelukast (0.15 mg/kg, iv) 30 min before, 1h after, or 4h after antigen challenge. In the control trial, the sheep received 0.9% saline, iv, at each of the above time points. The maximum decrease in tracheal mucus velocity seen in the control trial was 56±4% (mean ±SE) of baseline at 8h. Pretreatment with montelukast significantly protected against this reduction. However, treatment at 1 and 4h neither protected against nor reversed the allergen-induced fall in tracheal mucus velocity. We conclude that the early release of cysteinyl leukotrienes may contribute to the fall in tracheal mucus velocity that follows acute antigen challenge and that pretreatment with montelukast reduces this impairment.