ABSTRACT: Areas of immunocytochemically defined immunopathology are common in placentae from secondary recurrent spontaneous aborters. Endothelial cells of affected villi were found to be negative for the thrombomodulin natural anticoagulant pathway, and these cells were reactive with monoclonal antibodies to tissue factor and fibrin. Endothelial cells of normal villi adjacent to affected villi also were negative for thrombomodulin and positive for tissue factor and fibrin, but endothelium of normal villi distant to affected villi were thrombomodulin-positive, tissue factor-negative, and did not contain deposits of fibrin. These findings indicate that a loss of endothelial anticoagulant activity precedes the onset of immunopathology. This observation, coupled with the findings that fetal stem vessels normally lack the heparan sulfate proteoglycan-antithrombin III natural anticoagulant pathway and that normal cord blood contains a heparin-like anticoagulant, suggest that a failure of endothelial anticoagulation may be a primary event in the development of placental immunopathology.