We have determined the effect of prior inhalation of the LTD4 antagonist SK&F 104353 on the response to aspirin ingestion in six aspirin-sensitive asthmatic subjects (five women and one man 31 to 54 yr of age) in a randomized, double-blind, cross-over, placebo-controlled study. Pretreatment with inhaled SK&F 104353 (average nebulized dose, 893 micrograms) inhibited the response by a mean of 47% (p = 0.02). The inhibition was partial, ranging from 43 to 74% in five subjects. In the remaining subject, there was no effect of the drug on the asthmatic response. We conclude that the mechanism of aspirin-induced asthma is at least partially mediated by the leukotrienes in the majority of susceptible patients and that leukotriene antagonists may be useful in the treatment of aspirin-induced asthma.