The ability of haptenated subpopulations of epidermal cells (EC) to induce contact hypersensitivity (CH) in Syrian hamsters was investigated. Crude haptenated EC and haptenated EC enriched for Langerhans cells (LC) inoculated i.v. into hamsters induced CH that was equivalent in intensity to that induced by epicutaneous application of hapten. By contrast, haptenated EC, relatively depleted of LC, failed to induce CH hypersensitivity responses. Upon subsequent reimmunization of all animals with epicutaneously applied hapten, hamsters that had first received haptenated EC depleted of LC failed to respond in CH assays, indicating that these animals had been rendered unresponsive. These data suggest that haptenated LC are capable of inducing CH regardless of the route of inoculation, whereas haptenated EC, when depleted of LC, deliver a down-regulating signal via the i.v. route.