The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) can act as an antagonist to interleukin 1 (IL-1) bioactivities such as inhibition of fever production, thymocyte proliferation, and inhibition of release of acute phase inflammatory molecules from the liver. In this report we have found that epicutaneous application of alpha-MSH suppresses both the sensitization and elicitation limbs of the cutaneous immune response (CIR) to potent contact sensitizers like dinitrofluorobenzene (DNFB) or oxazalone (OX) in mice. Further, the loss of contact hypersensitivity due to applications of alpha-MSH could be reconstituted by either intradermal or intravenous injections of epidermal thymocyte activating factor (ETAF)/interleukin-1. Topical application of alpha-MSH did not cause an alteration in Ia+ dendritic cells (i.e., Langerhans cells) but did produce a significant reduction in the expression of Thy1.2 marker on the Thyl+ dendritic epidermal cells (Thy1+DEC). It has no effects on the phenotypic expression of asialo GM-1 on these same cells. These observations suggest that alpha-MSH, a peptide classically isolated from the pituitary but found in many other tissues and cells of the body, may represent an additional biologic modifier than can modulate suppression of the contact hypersensitivity responses to various haptens. However, the mechanisms by which alpha-MSH or potentially other peptides found in the skin produce these suppressive effects have not been elucidated.