We describe a substrain of BB rats, BB/Pfd, characterized by a loss of autoimmune potential soon after onset of diabetes. When fresh syngeneic (BB/Pfd) islets (6 islets/g body weight) were transplanted under the kidney capsule of diabetic BB/Pfd rats 1-2 weeks after diabetes onset (n = 14), no recurrence of diabetes occurred. When, however, islets were transplanted on the day of diabetes diagnosis (n = 16), 10 animals were able to destroy the transplant (P < 0.005 vs. previous group). Pancreatic biopsies taken at the moment of transplantation in both groups showed an almost complete disappearance of beta cells and also insulitis in the pancreata of the 1- to 2-week diabetic rats, while the acutely diabetic rats still conserved a certain amount of beta cells and a florid insulitis. The development of a general immune defect was not the cause of this nonrecurrence, since allogeneic islet grafts were easily rejected (7 of 8), nor was there a general defect in mounting immune memory, since second set skin grafts could be rejected in an accelerated manner (9.7 vs. 15.8 days). The development of suppressor mechanisms as cause for nonrecurrence could not be demonstrated, since transfer of lymphocytes taken from 1- to 2-week diabetic rats into acutely diabetic rats at the moment of syngeneic islet transplantation was unable to prevent recurrence of disease (6 recurrences in 10 animals). We conclude that in the BB/Pfd substrain, the autoimmune capacity wanes rapidly after the onset of diabetes. This loss of autoimmune potential is parallelled by a disappearance of insulitis in the native pancreas, but the exact mechanisms of the spontaneous reestablishment of self-tolerance remain unclear.