Factor XIII (FXIII) produces cross-linkages among fibrin molecules within fibrin clots. Its deficiency is related with bleeding diathesis or retardation of wound healing. We report the possibility that intense double filtration plasmapheresis (DFPP) is associated with decreased FXIII activity. Five patients with various primary diagnoses were treated with DFPP and their FXIII activity was measured. Coagulation test results remained almost normal, but FXIII activities declined to less than 20% of their initial value before starting DFPP and 10% after DFPP in most cases. The cases that received intense DFPP therapy exhibited profoundly decreased FXIII activity. The clinical course demonstrated that DFPP caused the FXIII decrease. Fortunately, with careful observation, none of the patients experienced fatal bleeding. Only one case required fresh frozen plasma and an open hemostatic procedure because of prolonged postoperative bleeding. In general, DFPP most efficiently removes substances with the following characteristics: adequate molecular weight; long half-life; and small extravascular distribution volume. The FXIII properties meet all these characteristics. Consequently, we should devote much attention to FXIII activity during DFPP because it cannot be estimated from the usual coagulation tests. Patients who receive DFPP therapy, especially intensified therapy, should have FXIII measured during the course of therapy. Results show that DFPP can decrease FXIII activity. For this reason we recommend the measurement of FXIII when patients receive intense DFPP therapy with albumin replacement.