Large deletions, frame-shifts and result in functional FVIII levels below 1%. Severe hemophilia A patients are treated with on-demand or prophylactic protein replacement therapy using plasma derived or recombinant FVIII concentrates. Point mutations and small in-frame insertions or deletions in the FVIII gene generally result in a moderate or mild hemophilia A phenotype with circulating functional FVIII plasma levels between 1–5% and 5–30% respectively. The molecular mechanisms that underlie moderate and mild hemophilia A include defects with respect to biosynthesis, impaired secretion, altered interaction with factor IXa, reduced binding to phospholipid membranes, impaired thrombin activation, impaired stability in the circulation or a reduced ability to associate with VWF in plasma. In addition to protein replacement therapy, mild or moderate hemophilia A patients can be treated with infusions of the vasopressin analogue desmopressin. Administration of DDAVP releases both VWF and FVIII in the circulation. The source of DDAVP-releasable VWF and FVIII has not been established. However, several lines of evidence suggest that FVIII and VWF are synthesized and stored within the same cell. While it is generally recognized that DDAVP releases VWF from WPBs, the origin and nature of the DDAVP-sensitive storage compartment of FVIII has not yet been defined. We and others have proposed that the DDAVP-induced rise of both FVIII and VWF argues for co-storage of both these proteins in WPBs. Pertinent to this point is our recent observation that VWF type 2N variants, despite a markedly decreased ability to bind to FVIII, drive co-trafficking of FVIII to VWF-containing granules. In addition, we have previously demonstrated that the FDA-approved Compound Library Tyr1680Phe FVIII variant is co-stored with VWF in WPBs despite its severely reduced interaction with VWF. This raises the question as to whether VWF co-storage of FVIII variants displaying a reduced ability to associate with VWF represents a general phenomenon in mild/moderate hemophilia A. We have therefore extended our initial observation regarding the Tyr1680Phe variant to a larger panel of mild/moderate hemophilia A causing FVIII variants, including amino acid replacements in the FVIII C1 and C2 domains. In addition, we now have used a quantitative approach to assess trafficking of FVIII to VWF-containing granules in HEK293 cells. Moreover, we addressed co-trafficking of GFPtagged as well as untagged FVIII variants in endothelial cells, with particular reference to the morphology of FVIII-containing WPBs. We demonstrate that point mutations in the C1 and C2 domains of FVIII can have diverse effects on its synthesis, secretion and ability to bind to VWF without loss in cofactor function, in agreement with previously published data. The ranking of VWF binding is the following: wild type.Arg2150His.Del2201.Pro2300Ser.Ser2119Tyr = Tyr1680Phe. Remarkably, notwithstanding their reduced capacity to bind to VWF and/or reduced levels of synthesis, substantial amounts of moderate/mild hemophilia A causing FVIII variants can be stored in VWF-containing granules.