We investigated the effects of immunotherapy (IT) on the early (ER), late (LPR), and rechallenge reactions (RCRs) to nasal challenge with antigen as well as on the cutaneous ER and LPR to intradermal skin challenge. Our expectation was that IT would have a preferential effect on the LPR, and our aim was to understand the mechanism. Twenty-one ragweed hay fever-sensitive subjects were treated with a moderate dose of antigen extract (maintenance dose of 1.94 micrograms of antigen E (Amb a I)) during a period of 8 months (total dose equivalent to 24 micrograms of antigen E), and 20 matched subjects received placebo injections in a double-blind manner. Both groups underwent identical nasal challenges and intradermal skin tests with ragweed-antigen extract both before (1985) and during (1986) IT. Symptom and medication diaries, recorded during seasonal exposure, and changes in specific serum IgE and IgG antibodies confirmed the efficacy of the administered IT dose. Between-group analysis revealed that IT significantly reduced the levels of histamine, TAME-esterase activity, and kinins, as well as symptoms of rhinorrhea and congestion generated during the ER to nasal challenge. Within-group paired analysis demonstrated ER, LPR, and RCR mediators and symptoms also to be reduced by IT. Surprisingly, the placebo-treated group demonstrated an increase in the ER. There was no decrease of the LPR without an antecedent decrease of the ER. IT did not clearly change the late cellular inflammatory response. In the case of skin challenge, IT significantly reduced the cutaneous ER. The reduction of the cutaneous LPR was more pronounced. We speculate that moderate-dose IT ameliorates seasonal symptoms of allergic rhinitis by reducing the ER, LPR, and RCR to antigen challenge but does not preferentially reduce the nasal LPR.