End Stage Renal Disease (ESRD) manifests hematologic, cardiovascular, inflammatory, and immunologic dysfunctions. Erythropoietin deficiency is present in ESRD leading to anemic states. ESRD patients receive regular/repeated administration of commercially available recombinant erythropoietin (r-E) (Epogen® Procrit® Patients treated with r-E have been known to develop thrombotic complications during r-E therapy. Antibodies to erythropoietin are generated in some patients and lead to erythropoietic aplasia. The mechanisms of the anti-erythropoietin antibody induced aplasia and reported hypercoagulability state in patients treated with r-E are not fully understood. Anticoagulant drugs such as heparin are used to reduce the incidence of thrombotic complications during r-E therapy. To understand pathogenesis leading to hypercoagulable state and its potential link with r-E treatment, blood samples taken from a group of 60 patients with ESRD were drawn prior to initiation of antithrombotic therapy. These patients on periodic hemodialysis were administered r-E 6–8 weeks prior to blood drawn. Anti-erythropoietin antibody titer, anti-phospholipid antibody (APA) titer, CRP levels, fibrinopeptide-A (FPA), nitric oxide (NO) levels, asymmetric 1,3-dimethylarginine (ADMA) levels, and thrombin activatable fibrinolytic inhibitor (TAFI) levels were measured. Five of 60 patients (8.3%) showed higher titers of anti-erythropoietin antibodies. Three of 60 patients (5%) exhibited positive titers of anti-phospholipid antibodies. Marked elevation of the CRP, FPA, NO, ADMA, and TAFI levels were noted in comparison to match controls. Patients with positive levels of anti-erythropoietin antibody titer (3 to 5 folds) exhibited a simultaneous elevation of FPA, CRP and TAFI suggesting the potential role of anti-erythropoietin antibody in mediating these responses. These observations indicate that ESRD patients treated with r-E are at a higher risk of developing thrombotic complications. The upregulation of NO and ADMA in these patients is suggestive of ongoing inflammatory processes. Anticoagulants such as low molecular weight heparins may be useful in the management of these patients.