Murine antibody responses to heterologous insulins are under H-2-linked immune response (Ir) gene control. We previously demonstrated that the immune response to insulin in Freund's complete adjuvant (CFA) can be specifically inhibited by prior injection of soluble insulin i.v. Unresponsiveness requires at least 4 days after i.v. injection to develop, and once induced, it lasts 4 wk or more. Unresponsiveness is caused by T cell, but not B cell, tolerance; furthermore, we have been unable to demonstrate any role for suppressor T cells in this unresponsiveness. The following experiments examine the nature of the T cell tolerance induced by i.v. injection of insulin, and the data suggest that helper T cells were not clonally deleted by this procedure. The functional activity of the tolerized T cells can be rescued by stimulation with insulin covalently complexed to the type 1 T-independent (TI-1) antigen, Brucella abortus. This observation suggests that tolerance induced by soluble insulin is due to clonal anergy rather than clonal deletion of helper T cells; thus, this system could provide a model for determining the cellular events involved in tolerance induction and reversal in helper T cells.