We directly measured the range of individual airway responses to aerosol and intravenous administration of histamine by using high-resolution computed tomography and then compared the heterogeneity in constriction responses between these two routes. Seven dogs were used for a total of eleven studies. Six of the seven dogs received intravenous histamine (100-300 micrograms/min) and five of the seven dogs received aerosolized histamine (0.01-3.0 mg/ml for 5 breaths). Data were analyzed using linear regression models calculating residual mean square values for each route of histamine as a measure of variability in the change in airway size. The residual mean square values for the absolute airway size after the aerosol and intravenous histamine challenges were 17.73 and 15.42, respectively, which were not significantly different [F(331,166) = 1.15, P = 0.32]. Also, there were no significant differences when we compared the log or the percent change in airway area for the two routes of administration. We conclude that the route of histamine administration does not significantly affect the heterogeneity of airway response, suggesting that the heterogeneity observed after the histamine challenge is predominantly controlled by local mechanisms in the airways.