We Investigated whether or not leukotrlene D. can influence the maximal degree of airway narrowing in normal humans by comparing the maximal responses to inhaled methacholine and LTD., and evaluating the interaction between both agonists. In 8 normal subjects, methacholine challenges were performed 24 h before and 24 and 72 h after a LTD. challenge. Doubling doses of methacholine (1.3 to 655 µmol) or LTD₄ (0.007 to 192 nmol) were inhaled by using a recently validated method. The highest dose of LTD₄ was followed by the maximal dose of methacholine. The response was measured by FEY₁ and volume history standardized partial expiratory flow-volume curves (V_40p), and was expressed as percent fall from baseline. All subjects reached a maximal response plateau to both agonists. The maximal response plateau to LTD₄ was systematically higher than to methacholine on the preceding day (mean difference, 13.4 and 12.7% fall for FEY₁ and V_40p, respectively) (p < 0.01). Addition of methacholine on top of the LTD₄ plateau caused a further increase In the response (mean, 8.8 and 4.8% fall, respectively) (p < 0.005). The maximal responses to methacholine at 24 and 72 h after the LTD. challenge were higher than at 24 h before (mean difference at 24 h, 4.0 and 8.5% fall for FEY₁ and V_40p, respectively, and at 72 h 5.7 and 9.3% fall) (p < 0.05). However, the provocative dose of methacholine causing a 10% fall in FEY₁ (PD₁₀) or a 40% fall in V_40p (PD₄₀) was not altered by the previous LTD₄ challenge test. We conclude that in normal humans in vivo the maximal degree of airway narrowing to LTD₄ is more severe than to methacholine. Moreover LTD₄ heightens the level of the maximal response to methacholine for a prolonged period of time, without affecting the position of the dose-response curve. This indicates that the leftward shift of the dose-response curve and the increased maximal airway narrowing in asthma are not determined by one and the same process.