Ninety-five dogs with spontaneous malignant lymphoma in chemotherapy-induced remission were treated with total-body irradiation (TBI) and bone marrow transplantation. Among 38 dogs treated with 8.4 Gy delivered at 4 cGy/min, 9 (24%) became long-term disease-free survivors. Ten of the 38 (26%) died of transplant-related complications and the actuarial relapse rate was approximately 65%. Forty animals were treated with higher-dose TBI (13.5 Gy). The higher-dose TBI led to an increased incidence of transplant-related deaths (55% vs. 26%) and did not reduce the actuarial relapse rate. Eight animals were treated with 8.4 Gy at 4 cGy/min, allogeneic marrow from unrelated donors, and posttransplant immunosuppression with methotrexate and cyclosporine. Of 8 animals, 6 died within 2 weeks of transplant of infection and 2 died later of graft-versus-host disease. Finally, 9 dogs were treated with 8.4 Gy at 4 cGy/min, autologous marrow, and posttransplant methotrexate and cyclosporine. Six of these animals died within 2 weeks of transplant. These studies thus demonstrated that dogs with malignant lymphoma in remission can be cured with high-dose TBI and autologous marrow transplantation, that increasing the total dose of TBI led to increased toxicity without a decrease in the relapse rate, and that post-transplant therapy with methotrexate and cyclosporine was poorly tolerated in these animals.