Crossed antigen-antibody electrophoresis was used to determine the electrophoretic properties of factor VIII/Von Willebrand (F. VIII/VW) protein in normal plasma using a specific rabbit antiserum against purified human factor VIII. The electrohoretic patterns in seven patients with severe Von Willebrand's disease in two different families were studied. In these patients the prolonged bleeding time was related to a functionally abnormal F. VIII/VW protein which was unable to induce platelet aggregation in presence of ristocetin. F. VIII/VW protein had an increased electrophoretic mobility in all the patients. The electrophoretic pattern was similar in different members of the same family but differed from one family to the other. Plasma samples collected after transfusion of normal cryoprecipitate to one member of the first family showed an increasing amount of F. VIII/VW protein, but even one hour after transfusion only one peak migration in an abnormal position was found. However, when mixed in vitro with normal plasma, the plasmas of the same patient showed two peaks, one in position of normal F. VIII/VW protein and one with increased electrophoretic mobility. These results suggest that normal F. VIII/VW protein transfused to recipients with Von Willebrand's disease synthesizing a functionally deficient factor undergoes a rapid alteration.