Previous studies have suggested that activation of the complement system might be a major mechanism for posttransfusion non-immunoglobulin (Ig) E-mediated anaphylactic reactions, but its causative effect has not been clearly demonstrated in human models. Serial plasma samples were collected from a patient with severe von Willebrand disease, IgG alloantibodies against von Willebrand factor (vWF), and a history of posttransfusion anaphylaxis. During an 18-day period the patient was treated with factor VIII-vWF concentrate and with recombinant factor VIII. Complement system activation was assessed from plasma levels of C4a, C3a, cleavage products of complement factor B, soluble terminal complement complex, C1 inhibitor and C4-binding protein, and the contact phase of coagulation was assessed from plasma levels of activated factor XII and cleaved high-molecular-weight kininogen. Plasma levels of antibodies to vWF and complement-fixing IgG-vWF complexes were also evaluated. Symptoms of anaphylaxis and signs of complement activation were present only when IgG antibodies to vWF were measurable during replacement with factor VIII-vWF concentrate (days 1 and 6). IgE, IgA, and IgM antibodies to vWF were not detectable in plasma at any time. Replacement with recombinant factor VIII (days 7 to 18) secured hemostasis and did not elicit anaphylactic reactions, and complement parameters did not significantly change even when antibodies to vWF reached peak plasma levels. This prospective study of a natural clinical model indicates a cause-effect relationship between formation of IgG-vWF complexes and massive complement activation in posttransfusion non-IgE-mediated anaphylactic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)