Hemophilia A is an X-linked hereditary bleeding disorder caused by deficient or defective coagulation factor VIII. Multiple molecular defects may affect factor VIII gene such as point mutations, premature stop codons, deletions, insertions and inversions. The most common sequence alterations leading to a severe disease condition are the partial gene inversion with a breakpoint in intron 22 of the factor VIII gene, responsible for about 40-50% of the severe hemophilia A cases. The aim of this work was genotyping of int22h-related rearrangements of factor VIII gene by Inverse shifting-PCR (IS-PCR) in Egyptian patients with hemophilia A in order to facilitate carrier detection and prenatal diagnosis. Our study was conducted on 30 Hemophilia A patients following up regularly at the Hematology Clinic, New Children Hospital, Cairo University, and revealed that among severe cases, 6/13 patients (46.1%) had intron 22 inversion, 3/13 patients (23.1%) had intron 22 deletion and 4/13 patients (30.8%) carried the wild type (normal) allele. Only one out of 10 patients (10%) with moderate disease was positive for intron 22 inversion, whereas the rest of moderate cases carried the wild type (normal) allele. All mild cases were negative for int22h-related rearrangements and carried the wild type (normal) allele. We concluded that the genotyping of int22h-related rearrangements of factor VIII gene by Inverse shifting-PCR (IS-PCR) can be used in molecular diagnosis of severe and moderately severe hemophilia A and it is able for rapid discrimination between inversions (type 1and 2) and deletions (type 1and 2) and duplication of intron 22. We suggest that the spectrum of intron 22 inversion/deletion in the Egyptian hemophilic patients is similar to that reported in other populations.