Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions. It is used as an immune-modulating therapeutic, but its molecular effects in human skin are largely unknown. We studied cellular and molecular characteristics of a recall response to 0.04% DPCP at 3-day (peak) and 14-day (resolution) time points using immune markers, reverse-transcriptase-PCR (RT-PCR), and gene array approaches. A peak response showed modulation of ∼7,500 mRNA transcripts, with high expression of cytokines that define all major effector T-cell subsets. Concomitant increases in T-cell and CD11c+ dendritic cell (DC) infiltrates were measured. The resolution reaction was characterized by unexpectedly high levels of T cells and mature (DC-lysosome-associated membrane glycoprotein positive (DC-LAMP+)) DCs, but with marked decreases in expression of IL-2, IFNγ, and other T cell-derived cytokines. However, negative immune regulators such as IDO1 that were high in peak reactions, continued to have high expression in resolution reactions. In the resolution reaction, ∼1,500 mRNA transcripts were significantly different from placebo-treated skin. These data suggest that the response to DPCP evolves from an inflammatory/effector peak at day 3 to a more regulated immune response after 14 days. This model system could be useful for further dissection of mechanisms of immune activation or negative immune regulation in human skin.