We studied the effect of the inhaled leukotriene D4 antagonist, L-648,051, on antigen-induced bronchoconstriction and nonspecific bronchial reactivity. Ten males with mild atopic asthma completed a double-blind, randomized, two-period, placebo-controlled cross-over study. For a 7-day period patients inhaled either placebo or 6 mg of L-648,051 four times daily. Bronchial reactivity to methacholine was measured at base line (day 1) and after 6 days, treatment (day 7). On day 8, after inhaling 6 mg of the antagonist (or placebo), the patients were challenged by inhaled antigen; they received an additional 6 mg of the antagonist (or placebo) 3 h later. Pulmonary function (forced expiratory volume in 1 s, FEV1) was measured serially through an 8-h post-antigen challenge. Nonspecific airway reactivity was again measured on day 9. Compared to placebo, L-648,051 treatment diminished the methacholine reactivity, on both day 7 (NS) and on day 9 (P < 0.05). In addition, the immediate and late bronchial responses to antigen challenge on day 8 were attenuated in the patients when treated with L-648,051. In the immediate phase (0-3 h postchallenge), the airway response was significantly reduced at all recordings between 20 min and 1 h postchallenge. In the late phase (3-8 h postchallenge), the pulmonary response was also reduced. However, the reduction was statistically significant only at the 5-h recording. The results suggest that sulfidopeptide leukotrienes are of importance for nonspecific airway reactivity, and that leukotriene D4 is a significant mediator in the immediate asthmatic reaction.