The effects of injecting human, rabbit, rat, or single-kidney homologous glomerular basement membrane (GBM) or autologous GBM, each in complete Freund's adjuvant (CFA), into 15- to 18-month-old sheep are compared. All sheep receiving heterologous GBM and 3 of 6 sheep receiving homologous GBM had anti-GBM nephritis, but such sheep did not bind autoantibodies or have Goodpasturelike lesions in their lungs. Sheep given injections of human GBM had autoantibodies to antigenic determinants shared by fetal or adult sheep and human GBM, by lung basement membranes, and by certain nonvascular basement membranes. Sheep given homologous GBM had two populations of autoantibodies: one was neither species- nor organ-specific; the other was sheep-specific. No sheep given autologous GBM had any evidence of anti-GBM autoantibodies or nephritis. Their kidneys were indistinguishable by histologic, immunohistologic, and functional studies from CFA-treated controls. Thus, sheep seem very tolerant to autologous GBM. These findings suggest that human anti-GBM nephritis may occur if the GBM is altered so that it becomes cross-reacting and induces autoantibodies, as does homologous GBM.