The natural anticoagulant pathway involving heparan sulfate proteoglycan and antithrombin III (ATIII) was studied in serial biopsies from 90 cardiac allograft recipients. The ATIII component of this pathway was identified immunocytochemically on venous endothelium and arterial smooth muscle cells and intima of normal donor hearts and stable allografts. Unstable grafts lacked vascular ATIII and contained fibrin deposits. Neither stable nor unstable grafts had ATIII-reactive capillary endothelium. Grafts with absent vascular ATIII could (1) result in death, (2) revert to an arterial/venous ATIII distribution or (3) develop ATIII-reactive capillary endothelium. The development of ATIII-reactive capillaries was associated with a survival advantage, and such reactivity seemed to be promoted by heparin.