Pollen immunotherapy exerts greater efficacy in the pollen season when the pollen count is not high than when it is high. Every pollen season, around half or more patients who have received pollen immunotherapy for >5 years are judged as good responders; those who have received immunotherapy for <5 years generally do less well. Therefore, the clinical response seems to depend on natural pollen counts and the duration of immunotherapy. In this study, peripheral blood mononuclear cells (PBMCs) were sampled before and during the pollen season to examine IL-4, IL-5, and IFN-γ levels. It was revealed that pollen immunotherapy could decrease IL-4 and -5 expression by pollen antigen-stimulated PBMCs. When patients under immunotherapy were divided into good and poor response groups, clinical effectiveness was related to the depressed level of IL-5 synthesis, but not to that of IL-4 synthesis. Our study suggests that a decrease of IL-5 expression during the pollen season is a key working mechanism of immunotherapy related to clinical effectiveness. In our patients, the incidence of systemic reactions was 5.8%/patient and <0.1%/injection. A higher incidence of systemic reactions was observed in patients with the presence or a past history of asthma, the presence but not a past history of atopic dermatitis, and higher levels of total IgE (>1000 U/mL). The incidence of systemic reactions in patients with 1 risk factor such as asthma, atopic dermatitis, and high IgE was 16.9%/patient and 0.1%/injection, whereas that in those without risk factors was 1.6%/patient and <0.1/injection.