To delineate the working mechanisms of immunotherapy (IT) (hyposensitization), the production of, and responsiveness to, histamine-releasing factor (HRF) was studied in four groups. These groups consisted of 32 newly diagnosed children with asthma, 40 good responders and 18 poor responders to IT (older than 2 years), and 15 healthy subjects. The results demonstrated (1) peripheral blood mononuclear cells of new patients produced a much greater HRF activity, either spontaneously or after stimulation, than did those of normal subjects, (2) the spontaneous HRF activity decreased significantly in good responders, whereas that of poor responders increased, (3) both the allergen (mite)- and mitogen (phytohemagglutinin [PHA])-stimulated HRF activity was decreased, although decrease was not significant, in good responders, but the activity was not changed in poor responders, (4) the granulocytes of new patients responded to HRF much more vigorously than did granulocytes of normal subjects. The responsiveness diminished significantly in both good and poor responders, although the magnitude of decrease was slightly greater in the former, (5) there was a positive correlation between PHA- and mite-stimulated HRF activity, mite-stimulated HRF activity and responsiveness to HRF, and plasma histamine level and responsiveness to HRF in the new patients, and (6) there was an inverse correlation between PHA-stimulated HRF production and responsiveness to HRF in good responders, but the correlation was positive in poor responders. Thus, IT is able to suppress the HRF activity, particularly the type of spontaneous synthesis, and responsiveness to HRF in clinically benefitted children with asthma, and this effect may be used to explain, partly, the efficacy of IT in a proportion of allergic patients.