Background: In experimental models, imidazoquinolines exhibit several immunomodulatory activities via Toll-like receptor signaling on cells of the innate immunity. Objective: The aim of our study was to investigate whether R-848 (Resiquimod), a small-molecular-weight synthetic compound belonging to the imidazoquinoline family and known for its ability to substantially delay the onset of recurrent genital herpes lesions in both animals and human beings, could influence, at least in vitro, the cytokine production profile of human hapten- or allergen-specific T cells. Methods: Ampicillin- and Der p 1–specific T-cell lines were derived from peripheral blood of allergic donors in the absence or presence of R-848 and assessed by flow cytometry at the single-cell level for their ability to produce IL-4 and/or IFN-γ. Results: R-848 induced both hapten- and allergen-specific circulating T cells, including T_H2 effectors, to produce IFN-γ and even to lose the ability to produce IL-4, thus shifting their phenotype of cytokine production to a type 0 (T_H0) or even T_H1 profile. This effect was associated with an increase in the production of IL-12, IFN-⍺, IL-18, TNF-⍺, IL-10, and IL-15 by CD14⁺ cells, as well as an increase in the proportions of IFN-γ–producing CD3^–CD16⁺ (natural killer) cells. Conclusions: These results suggest that R-848, and probably other imidazoquinolines, might be used as adjuvants in view of novel allergen-specific immunotherapeutic regimens for the treatment of allergic disorders. (J Allergy Clin Immunol 2003;111:380-8.)