Measurements were made of the effects of methoxyphenamine hydrochloride on histamine-, acetylcholine- and U46619-induced bronchoconstriction in pentobarbitone-anaesthetized guinea-pigs, and on histamine- and acetylcholine-induced contractions of guinea-pig ileum in vitro. Methoxyphenamine (20 mg/kg, i.v.) did not affect bronchoconstriction induced by acetylcholine or the thromboxane A2-mimetic U46619. However, it produced a parallel rightward shift [2.94-(1.79, 4.41) fold, 95% confidence limits in parentheses] of the curve relating bronchoconstrictor responses to log-dose of histamine at a total dose of 13 mg/kg, i.v., which was not significantly different from the shift [3.30-(1.93, 5.56) fold] produced by 3 micrograms/kg, i.v., of the histamine antagonist mepyramine maleate. Histamine-induced contractions of the isolated guinea-pig ileum were antagonized by methoxyphenamine (10(-5) to 10(-3) M). The histamine log-concentration-response curve was shifted to the right in a parallel manner by methoxyphenamine (10(-5) to 10(-4) M), without depression of maximum responses. However, at higher concentrations, maximum responses were reduced. The slope of the Schild plot was significantly different from -1. The degree of the rightward shift of the concentration-response curves to histamine, produced by 10(-5) M of methoxyphenamine [3.90-(2.83, 4.97) fold], was not significantly different from that produced by 3 x 10(-9) M of mepyramine [4.60-(2.86, 6.52) fold]. Methoxyphenamine, at concentrations of 10(-5) to 3 x 10(-4) M, had no significant effect on responses of guinea-pig ilea to acetylcholine (10(-9) to 10(-5) M). These results indicate that methoxyphenamine antagonizes the effects of histamine both in vivo and in vitro. In vitro studies indicate a noncompetitive antagonism.