Antigen challenge can elicit an allergic inflammatory response in the airways that involves eosinophils, basophils, and neutrophils and that is expressed physiologically as a late airway response (LAR) and airway hyperresponsiveness (AHR). Although previous studies have suggested that E-selectin participates in these allergic airway responses, there is little information concerning the role of L-selectin. To address this question, we examined the effects of administering an L-selectin-specific monoclonal antibody, DU1-29, as well as three small molecule selectin binding inhibitors, on the development of early airway responses (EAR), LAR and AHR in allergic sheep undergoing airway challenge with Ascaris suum antigen. Sheep treated with aerosol DU1-29 before antigen challenge had a significantly reduced LAR and did not develop postchallenge AHR. No protective effect was seen when sheep were treated with a nonspecific control monoclonal antibody. Treatment with DU1-29 also reduced the severity of the EAR to antigen. Similar results were obtained with each of the three small molecule selectin inhibitors at doses that depended on their L-, but not necessarily E-selectin inhibitory capacity. The inhibition of the EAR with one of the inhibitors, TBC-1269, was associated with a reduction in histamine release. Likewise, treatment with TBC-1269 reduced the number of neutrophils recovered in bronchoalveolar lavage (BAL) during the time of LAR and AHR. TBC-1269, given 90 min after antigen challenge also blocked the LAR and the AHR, but this protection was lost if the treatment was withheld until 4 h after challenge, a result consistent with the proposed time course of L-selectin involvement in leukocyte trafficking. These are the first data indicating that L-selectin may have a unique cellular function that modulates allergen-induced pulmonary responses.