Exercise-induced bronchoconstriction is caused, in part, by leukotriene (LT)D4 release in asthmatic airways. Asthmatics become refractory to exercise bronchoconstriction with repeated challenges, due to inhibitory prostaglandin release. The purpose of this study was to test the hypothesis that exercise refractoriness is caused by LTD4-induced inhibitory prostaglandin release. Fourteen stable asthmatic subjects with exercise-induced bronchoconstriction were studied. On the first 2 days, subjects underwent two challenges, 1 h apart, with either exercise or inhaled LTD4. Eight subjects then took part in three double-blind, randomized, placebo-controlled, crossover studies with flurbiprofen, a prostaglandin synthetase inhibitor, to determine whether cross refractoriness occurs between exercise and LTD4, whether flurbiprofen attenuates this effect, and whether flurbiprofen attenuates LTD4 tachyphylaxis. There was a reduction in the intensity of bronchoconstriction to the second challenge both with exercise (refractoriness) and with LTD4 (tachyphylaxis). The degrees of refractoriness and tachyphylaxis were correlated (r = 0.72, p = 0.005). Flurbiprofen attenuated LTD4 tachyphylaxis. Cross refractoriness occurred between exercise and LTD4, and flurbiprofen treatment also attenuated this effect. One hour after LTD4 challenge, the mean fall in FEV1 after exercise was 12.3% (%SEM 2.3) on placebo and 17.1% (%SEM 3.8) on flurbiprofen (p = 0.027). Similarly, 1 h after exercise, the LTD4 PC20 increased to 0.73 (%SEM 1.4) microgram/ml on placebo and 0.30 (%SEM 1.8) microgram/ml on flurbiprofen (p = 0.026). These results suggest that LTD4 released in asthmatic airways as a result of exercise stimulates inhibitory prostaglandin release, resulting in exercise refractoriness.