Ketotifen inhibits development of airway hyperreactivity in guinea-pigs exposed to PAF, (+/-)isoprenaline, immune complexes or endotoxin. Ketotifen is not a competitive histamine(H1) antagonist, so that it cannot be concluded that there is mandatory involvement of histamine in the development or expression of these forms of airway hyperreactivity. This conclusion has been reinforced by determining the efficacy of other histamine(H1) antagonists as inhibitors of PAF-induced airway hyperreactivity. When compounds were administered intravenously, at a dosage (1 mg/kg) which fully abolished responses to intravenous histamine, the observed rank order for inhibition of PAF-induced hyperreactivity was: ketotifen greater than cetirizine greater than acrivastine greater than KB-2413 greater than oxatomide greater than azelastine greater than terfenadine = astemizole = clemastine = mepyramine = loratadine = saline. Terfenadine may lack inhibitory activity because of a capacity to induce airway hyperreactivity in the guinea-pig. It can be concluded that inhibition of the development of airway hyperreactivity is not a characteristic of histamine(H1) antagonists.