Early experiments had shown that splenopentin, the active part of the splenic hormone splenin, stimulates the differentiation of virgin B- and T-lymphocytes and significantly enhanced the reconstitution of immune reactions after immune suppression. The present study investigates the influence of splenopentin on the course of the graft-vs-host reaction (GVHR). The experimental model used were adult hybrid mice which received intravenously parental spleen cells. During the GVHR which has an chronical course in the strain combinations used a short stimulatory phase is followed by a long-lasting immunosuppression detected by antibody formation against sheep erythrocytes. Furthermore, the splenomegaly in the first weeks after spleen cell injection changed to a drastic decrease of the spleen weight up to strongly beyond normal values. Continuous treatment with splenopentin significantly prevented both symptoms of the GVHR: The suppression of the antibody formation was diminished widely, and no loss of spleen weight occurred. Furthermore, during the stimulatory phase anti-DNA-autoantibodies were produced in the untreated animals, while the splenopentin therapy prevented this reaction. During the further course of the experiment no increase of autoantibody production was detected later on.