The purpose of the study was to investigate whether allergen-induced hyperresponsiveness to methacholine and an increase in airway smooth muscle (ASM) in Brown Norway (BN) rats could be mediated by LTD₄, an important mediator of allergic airway responses. Male BN rats, 8 to 12 wk of age, were sensitized with ovalbumin (OA). Rats were exposed 2 wk later to aerosols of saline (n = 6), OA (n = 8), or OA after pretreatment with the LTD₄ antagonist MK-571 (2 mg/kg intraperitoneally, n = 9), on six occasions at 5-day intervals. Airway responsiveness to methacholine (the concentration required to double pulmonary resistance, EC₂₀₀ Rl) was measured immediately before the first aerosol exposure and 2 days after the last exposure. ASM was quantitated by morphometry, and areas were standardized for size using the epithelial basement membrane length (BM). Following OA challenges EC₂₀₀ Rl decreased from 6.5 to 3.1 mg/ml ( p < 0.05) but did not change significantly after saline or OA exposures in MK-571-pretreated animals. ASM/BM² in the large airways was significantly greater, 3.41 ± 0.19 × 10⁻³, after OA compared with 2.35 ± 0.22 × 10⁻³ for saline exposures (p < 0.01). The ASM/BM² after OA exposures but with MK-571 pretreatment (2.75 ± 0.25 × 10⁻³) was intermediate in value. The results indicate that both the increase in airway responsiveness and the increase in ASM following repeated antigen exposures appear to be mediated predominantly by LTD₄.