Nafamostat mesilate (NM) has often been used as an anticoagulant instead of heparin during extracorporeal circulation under hemorrhagic conditions. However, reports of serious allergic reaction induced by NM have been accumulated. We report two cases of allergic reaction induced by NM during maintenance of hemodialysis. Case 1 was a 54-year-old woman, who had been on chronic hemodialysis for 24 years because of chronic renal failure due to lupus nephritis. After NM was used for hemodialysis prior to surgery for cervical spondylosis, the patient presented with fever. Case 2 was a 64-year-old woman with chronic renal failure due to nephrosclerosis. She had undergone hemodialysis for 9 years. Anaphylaxis appeared just after injection of NM during hemodialysis after vitrectomy. Both patients had histories of NM administration, but had never demonstrated an allergic reaction before. Among 35 cases reported previously, NM allergy was not characterized by the causes of renal failure, duration of maintenance dialysis and the membrane material of dialyser. However, most of these patients had a history of NM administration. Among 37 cases undergoing extracorponeal circulation, the features of NM allergy were classified into three types by the main symptoms, e.g., shock, eruption and fever. Patients demonstrating shock were prone to show less eosinophilia and a high positive rate on drug lymphocyte stimulation test. Patients with fever showed a marked elevation in CRP, and had a significantly longer history of dialysis. The number of hemodialysis patients has continued to increase rapidly, and the number of patients receiving NM during hemodialysis has been increasing. However, there is no currently valid method of predicting an allergic reaction, we should monitor patients for the possibility of an allergic response to NM.