To determine if a relationship existed between the site of airway obstruction and the mechanisms of exercise-induced asthma, we studied the predominant site of flow limitation, as determined by the mid-vital capacity ratios of maximal expiratory flow with air (Vmax air) and 80% helium-20% oxygen (Vmax He-O2), before and after physical exertion in 12 asthmatics. These observations were then related to the effects seen after vagal blockade and inhibition of mediator release. Five subjects increased Vmax He-O2/Vmax air ratios suggesting that the predominant site of flow limitation was in large airways. This group had their postexercise bronchospasm abolished by pretreatment with an anticholinergic agent. Seven subjects decreased their flow ratios indicating predominant small airway obstruction. Anticholinergic agents, although producing bronchodilation, did not alter their bronchospastic response to exercise. However, pretreatment with disodium cromoglycate did significantly diminish the response of this group. Thus the airway response to exercise in asthmatics is heterogeneous in terms of predominant site of flow limitation and this factor appears to relate to mechanisms.