Inhibitors to factor VIII (anti-F VIII) developing in patients with classic haemophilia have apparent specificity for the factor VIII procoagulant activity (VIII : C), rather than the factor VIII-related antigen (VIII : AGN) and von Willebrand factor (VIII : vWf) regions of the factor VIII complex. Since procoagulant function is absent following in vitro clotting, but serum retains VIII : AGN/vWf properties, we searched for differences in VIII : AGN and VIII : vWf of inhibitor serum that might relate to the presence of anti-F VIII. Rocket immunoelectrophoresis and the washed platelet ristocetin assay were performed on the plasma and serum of nine haemophiliacs with inhibitors, 23 non-inhibitor haemophiliacs and six normal subjects. Unlike normal and non-inhibitor haemophilic sera, that from five of nine inhibitor patients demonstrated absent VIII : vWf and significantly lower VIII : AGN (p less than 0.05). Furthermore, VIII : AGN of faster mobility was detected on crossed immunoelectrophoresis of the sera of three inhibitor patients. Thrombin clotting of plasma from haemophiliacs with high titer anti-F VIII was associated with a greater loss of VIII : vWf than seen with non-inhibitor haemophilic plasma. This effect was independent of the presence of platelets. These data indicate that in vitro clotting is associated with alteration in the serum VIII : AGN/vWf of some haemophiliacs with anti-F VIII.