Anti-Factor VIII (FVIII) antibodies represent a unique model to study the relationship between natural autoreactivity (natural antibodies to FVIII of healthy individuals) and disease-associated autoimmunity ('spontaneous' FVIII inhibitors of patients with anti-FVIII autoimmune disease) to a single human protein antigen. Although natural and disease-associated anti-FVIII antibodies are not readily distinguished based on the comparison of their isotypic distribution and epitope mapping, available studies of cross-reacting idiotypes suggest that FVIII inhibitors in patient's plasma encompass two populations of anti-FVIII antibodies - some antibodies result from the clonal expansion of B lymphocytes that exist previous to the treatment with FVIII and secrete anti-FVIII antibodies with properties similar to those of natural anti-FVIII antibodies present in healthy individuals, other inhibitors are produced by B cell clones that have undergone affinity-maturation and hypermutation of the V-regions of the antibodies they produce. The implications for the treatment of autoimmune patients with anti-FVIII inhibitors are discussed. © 2002 Elsevier Science B.V. All rights reserved.