The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.