Antigen contact via the alimentary tract prior to sensitization may result in systemic immunologic unresponsiveness ("oral tolerance"). The induction of oral tolerance seems an attractive strategy to combat undesired immune responses, such as allograft rejection and autoimmune and allergic diseases. We describe clear and reproducible sensitization to nickel in mice reared under nickel-free conditions. Hypersensitivity was induced by injecting nickel sulfate intradermally into the flank skin and elicited by injecting the metal salt into the pinnae of the ears. The effectiveness of orally induced hyporesponsiveness could be inferred from a low degree of hypersensitivity obtained with mice raised and maintained in cages with nickel-releasing covers and water nipples. This mouse model for the assay of nickel hypersensitivity was used for oral tolerance studies by administrating non-toxic doses of nickel sulfate in drinking water or intragastrically prior to sensitization. In these animals, the development of delayed-type hypersensitivity was suppressed in a dose-dependent way, and the hyporesponsiveness could be transferred by CD8+ cells. The antigen specificity of this oral tolerance could be demonstrated by the concomitant use of sensitization and challenge procedures for nickel and chromium. The hypersensitivity assay described provides a versatile, highly reproducible experimental model to study immunoregulation of oral tolerance to clinically relevant metal allergens.