Hemophilia A is caused by a wide spectrum of different mutations in the factor (F)VIII gene (F8), leading to deficiencies in coagulation FVIII activity and thus resulting in an inefficient blood clotting cascade. Large duplications comprising whole exons of F8 have been published for only a few cases so far.In the current study, we characterized the exact breakpoints for a total of 10 exon-spanning duplications of F8, including six novel duplications in seven unrelated patients. Seven breakpoints were located within long interspersed nuclear elements (LINEs), whereas short interspersed nuclear elements (SINEs) of the Alu-repeat type were observed at both breakpoint sites in four of the 10 duplications. At three breakpoints, microhomologies of 2 bp and 3 bp each could be identified.Duplication breakpoints in F8 were shown to be located in repetitive elements, especially SINEs or LINEs, but also in unique sequences. In addition, microhomologies, particular genomic features or sequence motifs, contribute to the duplication formation mechanisms.