Twenty patients suffering from birch pollen allergy received two or three courses of immunotherapy in successive years. In 9 patients, the fruit allergy improved; 4 patients reported no improvement. In 3 patients, the fruit allergy developed after beginning the immunotherapy. At the end of the 3 years, 16 of these patients were allergic to fruit, 13 of them to apple. After each preseasonal course of immunotherapy with tree pollen extract, a temporal and parallel increase in the titers of IgE antibodies to birch pollen allergens and apple allergens were observed. In contrast, only the titers of birch pollen allergen specific IgG and IgG4 increased, whereas apple allergen specific IgG and IgG4 did not, or only very slightly. In Western blot studies, IgG4 antibodies bound to more components of apple extract than birch pollen extract. On the average, IgG4 antibodies recognize more components of apple and birch pollen extracts than do IgE antibodies. In histamine release studies, the sensitivity of washed leukocytes to birch pollen extract decreased significantly during the observation time. However, the difference between apple extract-induced histamine release before and after immunotherapy was not significant. None of the immunological parameters investigated here correlate well with severity or prognosis of the fruit (apple) allergy. The clinical improvement of pollinosis was associated with a rise in birch pollen specific IgG4 antibody titers and a decrease of allergen-induced histamine liberation. Beside improvement of the fruit allergy in 56% of the cases, the courses of apple specific IgE and IgG4 antibody titers seem to indicate a slight sensitization against apple allergens.