BACKGROUND: Histamine released from activated mast cells and basophils is an important mediator in allergy. Therefore, antihistamines are efficiently and widely used to suppress allergic symptoms. OBJECTIVE: This study evaluated the role of antihistamines in sensitization against allergens and in the efficiency of allergen-specific immunotherapy. METHODS: CBA mice were sensitized and de-sensitized with bee venom allergen extracts and the major allergen phospholipase A2. Clemastine was used to test the effect of a histamine-1 receptor antagonist on the immune responses to phospholipase A2. RESULTS: The results demonstrated that sensitization against bee venom was strongly enhanced during treatment with antihistamines. Clemastine increased IgE production while decreasing IgG2a production against bee venom. This T-helper type 2 shift of the humoral response appeared to be caused by reduced IFN-gamma and enhanced IL-4 secretion from allergen-specific T cells. We also found reduced TNF-alpha, IL-6 and major histocompatibility complex class-II expression by macrophages. In sensitized mice, the efficiency of allergen-specific immunotherapy was reduced by clemastine treatment. CONCLUSION: Antihistamines may enhance allergic sensitization and reduce the efficiency of allergen-specific immunotherapy. Future studies will need to demonstrate to what extent pre-medication with antihistamine also affects allergen-specific immunotherapy in humans.