In Japan, about a quarter of the population has Japanese cedar pollinosis. One promising treatment is sublingual immunotherapy, which is under clinical investigation in Japan and not yet covered by the national health insurance system. Since 2005, we have treated more than 200 patients with Japanese cedar pollinosis. We found that sublingual immunotherapy is more effective than drug treatment, but less effective than subcutaneous immunotherapy. Moreover, patients receiving sublingual immunotherapy or subcutaneous immunotherapy use fewer concomitant medications than patients receiving drug treatment. Therefore, sublingual immunotherapy seems to be effective and associated with decreased drug use. The effect of sublingual immunotherapy seems to increase with increasing duration of treatment; the treatment seems to be more effective when continued for ≥4 years than when discontinued after 3 years. We aimed to elucidate the mechanism of action of sublingual immunotherapy. We found that sublingual immunotherapy increases the percentage of interleukin (IL)-10–producing inducible regulatory T cells, and that IL-10 is involved in the immune response to Japanese cedar pollen. Furthermore, levels of antigen-specific immunoglobulin G4 are increased in the cedar pollen season in patients receiving sublingual immunotherapy, and serum levels of IL-33 are increased in non-responders. Our findings should contribute to the further development of sublingual immunotherapy for Japanese cedar pollinosis.