Airway responsiveness to histamine in man may be determined by the smooth muscle sensitivity to histamine or to the interaction between vagal nerve input and smooth muscle sensitivity. We have compared in vivo responsiveness to histamine with in vitro smooth muscle sensitivity to histamine in 20 non-asthmatic patients and one asthmatic patient undergoing thoracic surgery. Histamine responsiveness was assessed in the first 10 non-asthmatics without atropine pretreatment, in the second 10 after atropine pretreatment, and in the asthmatic patient both with and without atropine. In vivo responsiveness was also measured in 10 normal subjects and 10 asthmatic patients not undergoing surgery. Results were expressed as the provocation concentration (PC) causing a decrease in FEV1 of 20% (PC20FEV1) and in specific airways conductance of 35% (PC35SGaw), and in terms of maximal expiratory flow at 35% vital capacity, measured from the partial (V35(P] and complete (V35(C] flow volume curves of 35% (PC35V35(P); PC35V35(C]. In vitro smooth muscle sensitivity to histamine of bronchial tissue obtained at thoracotomy was expressed as the concentration causing a 50% maximum contraction (EC50) and as the maximum tension generated. There was considerable variation between patients in the in vivo responsiveness but a relatively narrow range for in vitro responses. There was no significant correlation between in vivo responsiveness, either with or without atropine pretreatment, and in vitro results. The asthmatic patient showed hyperresponsiveness in vivo but but not in vitro. These results suggest that in vitro airway smooth muscle sensitivity to histamine is not the sole determinant of in vivo airway responsiveness and that this lack of relationship is not explained by the influence of vagal nerve input on in vivo measurements. The results in the asthmatic patient suggest that airway hyperresponsiveness may be an in vivo phenomenon which is not related to a primary abnormality of airway smooth muscle.