Syngeneic graft-versus-host disease has been shown to occur in syngeneic rat radiation chimeras after treatment with a short course of CsA. However, data concerning this model have been controversial in murine systems. We have successfully induced a GVHD-like syndrome in syngeneic mouse radiation chimeras treated transiently with CsA. Lethally irradiated (950 rads) DBA/2 mice were reconstituted with syngeneic bone marrow and treated daily, i.p. with 15 mg/kg CsA in olive oil for 21 days. Within 1 week after discontinuing CsA, animals developed clinical signs of GVHD including runting, hunched posture, and severe diarrhea. This disease was fatal for greater than 80% of treated animals within 4 weeks after cessation of CsA. Furthermore, the induction of syngeneic GVHD did not appear to be linked to a particular MHC haplotype. Histologically, there was pronounced lymphoid atrophy of the spleen and thymus. Sections of large intestine showed an acute inflammatory process involving the mucosal layer ranging from single-cell destruction to complete mucosal ulceration. This murine model of GVHD should provide new opportunities for studying the development and regulation of autoimmune processes.