The oral administration of antigens is one of the means of inducing tolerance in adult mammals. In this report, the role of gamma delta T cells in the induction and maintenance of orally-induced tolerance to ovalbumin was investigated. The injection of a monoclonal anti-gamma delta T cell monoclonal antibody blocked the induction of oral tolerance, because the secondary immune responses to ovalbumin in these animals were comparable to the corresponding responses in ovalbumin-immunized control mice. Furthermore, depletion of gamma delta T cells either in vivo or in vitro abolished already established oral-tolerance. The fact that the state of tolerance could be adoptively transferred to naive recipients by CD3+ alpha beta- gamma delta + spleen cells from tolerant mice. These results suggest that systemic oral tolerance is induced and actively maintained by mechanisms involving gamma delta T cells.