Allergic contact dermatitis is a T cell-mediated delayed type hypersensitivity reaction that occurs upon hapten challenge in sensitized individuals. The inflammatory response in classical allergic contact dermatitis requires both a sensitization phase and an elicitation phase responsible for the recruitment and activation of specific T cells at the site of hapten skin challenge. Conversely, previously unsensitized patients may develop a "primary allergic contact dermatitis" after the first skin contact with potent contact sensitizers leading to a skin inflammation with all the features of classical allergic contact dermatitis. In this study we used an experimental murine model, referred to as contact hypersensitivity, to study the pathophysiology of primary allergic contact dermatitis and its relationship to classical allergic contact dermatitis. We show that one epicutaneous application of a nonirritant dose of hapten (2,4-dini-trofluorobenzene, fluorescein isothiocyanate) was sufficient to induce an optimal allergic contact dermatitis reaction at the site of primary contact with the hapten without subsequent challenge. As in classical allergic contact dermatitis, the skin inflammation in primary allergic contact dermatitis was mediated by interferon-gamma producing, CD8+ effector T cells that were induced in the draining lymph nodes at day 5 postsensitization and downregulated by CD4+ T cells. Reverse transcription-polymerase chain reaction analysis revealed that the primary allergic contact dermatitis reaction was mediated by a recruitment of CD8+ T cells at the sensitization skin site at day 6 postsensitization. Analysis of the fate of the hapten fluorescein isothiocyanate applied once on the skin revealed its persistence in the epidermis for up to 14 d after skin painting. These results suggest that the development of primary allergic contact dermatitis (i.e., without secondary challenge) is associated with persistence of the hapten in the skin, which allows the recruitment and activation of CD8+ T cells at the site of the single hapten application.