Allografts of pancreatic islets of Langerhans were induced to survive for an indefinite period in diabetic mice if, at the time of engraftment, the mice received a single course of treatment with a monoclonal antibody directed against the L3T4 determinant, a nonpolymorphic cell surface glycoprotein present on the cell surface of the murine T helper-inducer lymphocyte subset. This treatment allowed the survival of islets of Langerhans transplanted across a major histocompatibility barrier without additional immunosuppression. The results demonstrate that the lymphocyte subset defined by the expression of the L3T4 molecules is central to the induction of allograft rejection and provides a model for tolerance induction for organ allograft transplantation.