Hemophilia A is an X-linked bleeding disorder resulting from deficiency in coagulation factor VIII. Numerous genetic variants (>2000) affecting the F8 gene have been implicated as causative of hemophilia A. These include structural variants (SVs) such as copy number variants (CNVs) and large intra-chromosomal inversions. For the vast majority of patients, causative variants can be identified using targeted sequencing of F8 coding regions and/or the use of methods which detect known SVs (e.g. inverse shifting PCR, long-range PCR, MLPA). However, these approaches fail to explain 1-3% of hemophilia A cases. In this study, we specifically performed SV analyses using whole genome sequencing (WGS) data from 11 cases of severe hemophilia A (factor VIII level < 1%) that remained genetically unexplained after exhausting available laboratory testing methods. These cases were selected from the My Life, Our Future (MLOF) hemophilia study recently sequenced by the NHLBI TOPMed program. SV analyses of the F8 genomic region revealed previously undetected deletions and inversions in 6 out the 11 cases. In these 6 samples, SV calls were supported by multiple sequencing reads (> 25 reads) and multiple types of read evidence (read depth, paired-end and/or split read evidence). Two deletions within intron 6 were detected in a single hemophilia A case, a finding which suggests F8 intron 6 may contain one or more regulatory elements critical for F8 expression. Three distinct large inversions predicted to disrupt the F8 structural gene were detected in five other cases; one case with a 720Kb inversion with breakpoints in F8 intron 6 and SPRY3 intron 1, one case with a 20Mb inversion with breakpoints in F8 intron 1 and INTS6L intron 8, and three cases with a 7.4Kb inversion with breakpoints in F8 intron 25 and the SMIM9 intron 1. These events have not been reported in hemophilia and were also not present in the larger, sequenced My Life, Our Future dataset (N=2186), supporting these SVs as novel and likely causative of severe hemophilia A. We predict additional deleterious SVs remain to be discovered in unexplained cases of hemophilia. This work further demonstrates dedicated analyses for SVs originating in non-coding regions should be considered in genetic studies of diseases caused by loss-of-function variants.