Leukotriene D, (LTD4) is a potent bronchoconstrictor that may play an important role in asthma. To better characterize the effect of LTD4 on human airways, normal, rhinitic, and asthmatic subjects underwent inhalation challenge tests with LTD4 and methacholine. In all subjects increasing concentrations of LTD4 produced a parallel decrease in specific airway conductance and flow at 30% of vital capacity measured from a partial forced expiratory maneuver (V30P). These changes occurred independent of any decrease in FEV1 or increase in functional residual capacity. The airway response to LTD4 was maximal within 2 to 3 min, persisted for approximately 30 min, and resolved over 1 to 3 h. Late effects were not seen. Rhinitic subjects were 3 to 5 times (p less than 0.01) and asthmatic subjects were 25 to 100 times (p less than 0.001) more sensitive than were normal subjects to LTD4. All 3 groups of subjects were 250 to 850 times more sensitive to LTD4 than to methacholine. Significant correlations were found between the concentration of LTD4 and the concentration of methacholine that produced a 35% decrease in specific airway conductance (r = 0.874; p less than 0.006) and a 30% decrease in V30P (r = 0.751; p less than 0.04). These results confirm that LTD4 is a potent bronchoconstrictor in humans, with a rapid onset of action and a prolonged effect. In contrast to previous reports, we found that LTD4 has an equal effect on both large and small airways and that both asthmatic and normal subjects have the same degree of increased sensitivity to LTD4 as to methacholine.