Histamine release after antigen inhalation was studied in 12 dogs sensitive to nematode antigens. In 19 experiments, histamine was detected in arterial plasma after antigen inhalation; its concentration was correlated with changes in airflow resistance of the respiratory system (Rrs) (per cent change above control equals 132.3 plus 250 log histamine concentration). Histamine was released from the lung and was not attributable to the concomitant hypoxia. In 6 dogs given aerosols of dilute antigen and in 4 dogs given aerosols of compound 48/80, Rrs increased significantly, but no histamine was detected. Histamine may have been released close to airway receptors, inducing bronchoconstriction, but in amounts undetectable in arterial plasma. In 6 dogs, administration of 48/80 caused partial depletion of histamine stores but prevented the response to antigen inhalation in only one of 6 dogs tested. The close correlation between arterial histamine concentration and Rrs, the qualitatively similar response to antigen and 48/80 aerosols, and the inhibition of the response to antigen when histamine was depleted completely from the lung tissues suggests that chemical mediators are critically important in antigen-induced airway reactions.