We examined the dose-response curves to methacholine in 6 normal subjects and 13 asthmatics by simultaneous assessment of respiratory resistance (Rrs) and anatomic dead space (VDan). Methacholine was continuously inhaled in stepwise incremented concentrations during tidal breathing until a nearly twofold increase in respiratory resistance (Rrs) was observed. Large airway response was determined by VDan, and overall airway response was determined by Rrs. Small airways response was inferred from Rrs when the decrease in VDan was slight. Respiratory resistance was measured with the 5-Hz oscillation technique, and the VDan was measured by Langley's method (14) with CO2 as the test gas, and both were recorded simultaneously breath by breath. In the normal subject, VDan decreased by 28 +/- 7% (mean +/- SD) and Rrs increased simultaneously by 100%, suggesting a large airways responder. Five asthmatics were large airway responders in a manner similar to that of the normal subjects, but in 8 asthmatics, VDan decreased by 10% or less, whereas Rrs increased by 100%, suggesting that the increase in Rrs was due to an increase in small airways resistance (small airways responder). In the asthmatic subjects, small airways responders showed more hypersensitivity than did large airways responders (p less than 0.01). These results suggest that the site of airway response is one of the determining factors in bronchial hypersensitivity.