Cyclosporine-induced graft-versus-host disease has been described in lethally irradiated rats and mice following syngeneic bone marrow reconstitution. To further study this apparently CsA-restricted phenomenon, we followed reported protocols by administering CsA orally at 50 or 100 mg/kg/day to irradiated, syngeneically reconstituted C57B1/6 mice. No clinical evidence of GVHD was observed for more than 8 weeks after CsA discontinuation. Ear biopsies and circulating immunoglobulin levels 2-4 weeks after stopping CsA failed to demonstrate histological or serological evidence of GVHD, respectively, compared with mice allogeneically reconstituted with Balb/c marrow. To further follow a previous report, CsA 50 mg/kg/day orally or 10 mg/kg/day intraperitoneally was given to normal C57B1/6 mice prior to using their spleen or bone marrow cells for reconstitution of lethally irradiated syngeneic mice. Clinical monitoring and histological examination of recipients 2-5 weeks after reconstitution again failed to confirm GVHD. Thus our results were uniformly negative in attempting to reproduce syngeneic GVHD in mice. Existing data on rats and humans are reviewed, showing that syngeneic or autologous GVHD is not CsA-restricted and that the syndrome could be equated to the chronic form of GVHD found in rats and patients after allogeneic bone marrow transplantation.