We have compared the effects of the leukotriene (LT) D4 antagonist L-649,923 and placebo on the airway response to antigen challenge in eight men with mild asthma known to have both an early and late response to inhaled antigen. Subjects ingested 1000 mg of L-649,923 or placebo in a randomized, double-blind protocol and, two hours later, inhaled the dose of antigen known to induce a 20% fall in FEV1. Pulmonary function (specific conductance, FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity) was measured at intervals before and up to 9 hours after antigen. FEV1 fell in one subject after L-649,923 ingestion. L-649,923 in the other seven subjects caused no change in baseline pulmonary function, a small reduction in the early response to antigen for FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity but not for specific airway conductance (six subjects only) and no effect on the late response. The mean maximum fall in FEV1 in the early response was 1.35 L after L-649,923 ingestion and 1.78 after placebo ingestion. This relatively small degree of protection by L-649,923 suggests either that L-649,923 is not a sufficiently potent antagonist to diminish the effect of endogenous LTD4 in vivo or that LTD4 does not play a major role in the airway response to antigen challenge.