BACKGROUND The cellular basis for the mechanism of specific hyposensitization is still unclear. OBJECTIVE We prospectively studied the effect of immunotherapy on allergen-induced proliferation and Fc epsilon R2/CD23 expression of lymphocytes. METHODS Mononuclear cells prepared from the peripheral blood of 22 patients with grass pollen (GP) allergy before, during, and after a preseasonal immunotherapy period with GP were stimulated with GP or control antigens. Tritiated thymidine uptake and percentage of CD23+ B cells were determined daily during days 6 to 8 and compared with lymphocyte responsiveness of 11 only symptomatically treated atopic patients and 14 nonatopic individuals. RESULTS GP-induced lymphocyte proliferative response of both hyposensitized and symptomatically treated GP-allergic patients decreased markedly before the pollen season and rose again after seasonal allergen exposure, whereas a long-lived decrease in GP-induced Fc epsilon R2/CD23+ B cells was only observed in GP-treated patients. Alterations in Fc epsilon R2/CD23 expression were closely related to changes in symptoms and medication requirement during the following pollen season. In contrast, immunotherapy had no effect on Fc epsilon R2/CD23 expression of B cells without stimulation or on B cells cultured in the presence of control antigens. CONCLUSIONS Because Fc epsilon R2/CD23 expression on B cells is antagonistically regulated by the cytokines interleukin-4 and interferon-gamma, the decrease of allergen-induced Fc epsilon R2/CD23+ B cells indicates an altered cytokine secretion pattern of the allergen-specific T lymphocytes with a predominance of interferon-gamma.