Treatment of chronic homologous disease, induced in young adult (C57BL/6 X DBA/2)F1 mice by injections of C57BL/6 spleen cells, was attempted with four agents: 6-mercaptopurine (6-MP), prednisone, methotrexate and total body X-radiation. 6-MP caused acceleration of the disease, regardless of dosage or timing of administration. Prednisone ameliorated homologous disease only when given at the same time as the parental cells. Methotrexate treatment suppressed the disease only when given after the parental cells, at a time when active disease is ordinarily expected. Total body X-radiation (400 r) led to extreme susceptibility to the graft-versus-host reaction, even if given 2 weeks before or 60 days after the parental cells. However, a period approximately 3 weeks after administration of parental cells was radioresistant in that no acceleration of the disease occurred. The accelerating effect of 6-mercaptopurine could not be reversed by administering isologous spleen cells. Amelioration of homologous disease by methotrexate was associated with the acquisition of durable specific immunological tolerance of host antigens by the injected parental cells.