Both exercise and histamine inhalation cause bronchoconstriction in asthmatic subjects. Repeated challenges with both stimuli cause less bronchoconstriction. Exercise refractoriness and histamine tachyphylaxis may occur through release of inhibitory mediators in the airways. The purpose of this study was to determine whether prior challenge with exercise or histamine reduced the subsequent bronchoconstriction to the opposite challenge. Eight asthmatic subjects with exercise bronchoconstriction were studied on 4 study days. On each study day, two consecutive tests were separated by 1 h as follows: on Day 1, two exercise challenges; on Day 2, two histamine inhalation tests; on Days 3 and 4, a histamine test was followed by an exercise challenge or an exercise challenge was followed by a histamine test. On Day 1, the mean fall in the FEV1 after the initial exercise challenge was 22.13% (SD, 7.12%); after the second exercise challenge, 1 h later, it was 11.13% (SD, 10.69%) (p less than 0.005). On Day 2, the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was 1.68 mg/ml (%SD, 2.02) for the first test and 2.68 mg/ml (%SD, 1.99) for the second test 1 h later (p less than 0.005). However, after exercise bronchoconstriction, the histamine PC20 was 1.88 mg/ml (%SD, 2.03), not different from the control value (p less than 0.5). In contrast, the fall in FEV1 after exercise after prior inhalation of histamine was 15.63% (SD, 10.0%) compared with 23.13% (SD, 8.6%) on the control day (p less than 0.005). Therefore, inhibitory mediators released during histamine inhalation can cause exercise refractoriness; however, the converse is not true.