Recent reports have suggested that chemical-induced allergic contact dermatitis may not be a traditional type IV hypersensitivity, in part due to the dual irritant and antigenic properties of sensitizing chemicals. In order to investigate the contribution of these properties to the molecular and cellular mechanism underlying allergic contact dermatitis, we evaluated oxazolone-induced changes in cell populations and cytokine production in the dermis of transgenic mice with impaired innate immunity (the FcγR subunit knockout mouse), and absent specific immunity (the athymic mouse), and the appropriate B6,129F2 and C57BL/6 control mice. Oxazolone and croton oil were applied in a single sensitizing dose, or in sensitizing and challenge doses, and the dermal response was evaluated by immunohistochemistry. In the wild type mice, with or without sensitization to oxazolone or croton oil, we observed mixed Th1/Th2 cytokine production and both CD4⁺ and CD8⁺ T lymphocytes; however, the neutrophil was the predominant cell in the dermis, even 72 h after final chemical application. Athymic mice displayed a similar neutrophil response with moderate Th1/Th2 cytokine production, and FcγR subunit knockout mice exhibited very mild dermatitis when treated with either oxazolone or croton oil. These results provide support for the hypothesis that allergic contact dermatitis is not a classic delayed type hypersensitivity, demonstrate the importance of the interaction between the irritant and antigenic properties of sensitizing chemicals in the development of allergic contact dermatitis, and suggest that the irritant effect of chemicals may be mediated through the cutaneous innate immune system.