Terfenadine (Seldane) is a new, highly potent H1 histamine receptor antagonist that in clinically effective doses is free of side effects. Because the low potency and specificity of many H1 receptor antagonists have made it difficult to define the precise role of histamine as a bronchoconstrictor mediator in asthma we have used terfenadine to define the degree and selectivity of H1 blockade that can be achieved in asthmatic airways. In a double-blind study, 9 asthmatic patients received placebo or terfenadine 60, 120, and 180 mg on separate days followed 3 h later by bronchial provocation with increasing concentrations of either histamine or methacholine. Terfenadine at 60, 120, and 180 mg produced significant bronchodilation with increases in FEV1 above baseline of 9.0, 9.5, and 10%, respectively (p less than 0.05, p less than 0.01, p less than 0.01). All 3 doses of terfenadine displaced the histamine-FEV1 concentration response curves in a parallel fashion to the right in all subjects. When the degree of protection against histamine is expressed as a concentration ratio, terfenadine 60, 120, and 180 mg displaced the response curves by factors of 14.8 +/- 4.6, 22.9 +/- 6.7, and 34.3 +/- 8.4. In contrast to its effect on histamine-induced bronchoconstriction, terfenadine failed to protect the airways against the constrictor effect of inhaled methacholine. Thus, terfenadine is a much more potent and selective H1 receptor antagonist in asthmatic airways than previously available antihistamines and should provide a powerful tool to define the contribution of histamine as a bronchoconstrictor mediator in asthma.