Previous reports have shown that elevated polyamine biosynthesis is sufficient to promote skin tumorigenesis in susceptible mouse strains. We hypothesized that increased activity of epidermal ornithine decarboxylase (ODC), a key regulatory enzyme in polyamine biosynthesis, may suppress the cutaneous immune response in addition to stimulating proliferation. Using an ODCER transgenic mouse model in which ODC is targeted to the epidermis, we examined the effect of ODC overexpression in keratinocytes on a classic contact hypersensitivity (CHS) response. Compared with normal littermate mice, ODCER transgenic mice showed reduced ear swelling, reduced neutrophil infiltration, and decreased migration of fluorescein isothiocyanate-loaded dendritic cells (DCs) to draining lymph nodes following hapten elicitation of CHS. In addition, elevated epidermal ODC activity suppressed the levels of cytokines keratinocyte-derived chemokine, monocyte chemoattractant protein-1, interleukin-6 (IL-6), and IL-10. Adoptive transfer of lymphocytes from sensitized ODCER transgenic or normal littermate mice to naive ODCER transgenic or wild-type mice indicated that elevated epidermal ODC activity suppresses both the sensitization and elicitation phases of CHS. The specific ODC inhibitor, α-difluoromethylornithine, abrogated all suppressive effects of ODC in CHS reactions. Collectively, these data suggest that the immunosuppression promoted by increased epidermal ODC is mediated by a reduction in cytokine levels, which suppresses DC migration and reduces immune cell infiltration to the site of hapten application.