Background. Tolerance is gaining momentum as an approach to reduce lifelong immunosuppressive therapy while improving transplant longevity. Anti-CD3 immunotoxin (IT), FN18-CRM9, has potential to induce tolerance owing to its exceptional ability to deplete sessile lymph node T cells. However, if initiated at the time of transplantation, α-CD3-IT alone elicits a proinflammatory cytokine response, precluding establishment of tolerance. Methods. Four groups of rhesus monkeys received kidney allografts and immunosuppression. Three groups received α-CD3-IT alone or α-CD3-IT supplemented with 15-deoxyspergualin (DSG) and/or methyl-prednisolone (MP). One group received α-CD3-monoclonal antibody with DSG and MP. Cytokines were measured by enzyme-linked immunosorbent assay. Results. Supplementing peritransplant α-CD3-IT treatment with a brief course of DSG and MP promoted rejection-free kidney allograft acceptance in 75% of macaques followed for up to 550 days. Among those given α-CD3-IT alone or with MP, none were long- term survivors. Tolerance developed after α-CD3-IT, DSG, and MP treatment, but not when the unconjugated α-CD3 monoclonal antibody was substituted for IT. Systemic production of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α induced after peritransplant α-CD3-IT was prevented only in animals given DSG. Despite high levels of interleukin (IL)- 12 in the first month after transplant, tolerant recipients exhibited IL-12 resistance, as evidenced by baseline plasma levels of IFN-γ but elevated IL- 4 DSG was shown to inhibit IL-12-driven IFN-γ production by a mechanism associated with inhibition of nuclear factor κ-B. Conclusions. In this model, peritransplant induction of tolerance is promoted by efficient elimination of sessile lymph node T cells and control of the proinflammatory IFN-γ response by a mechanism that appears to involve resistance to IL-12.