OBJECTIVE Recombinant DNA-derived clotting factor VIII concentrates (rFVIII) potentially have safety advantages over plasma-derived products. Removal of the B domain of the FVIII molecule does not seem to reduce the procoagulant activity and improve the efficiency of the manufacturer. However, when used, clinically possible differences in hemostatic efficacy between the full-length (FL) and B domain-deleted (BDD) molecules have emerged. This article predicts the impact that differences in the pharmacokinetic behavior between BDD- and FL-rFVIII may have on bleed prophylaxis in hemophilia A. METHODS Published data on the pharmacokinetic and biological effects of FL- and BDD-rFVIII were examined and used well-established proven pharmacokinetic modeling applied to therapeutic target plasma concentrations of FL- and BDD- rFVIII. RESULTS Biochemical differences between the 2 molecules in standard laboratory assays can be shown and in vivo BDD-rFVIII appears to show a shorter half-life possibly because of greater susceptibility to proteolytic degradation. Theoretical modeling demonstrates that if patients switch between FL-rFVIII to BDD-rFVIII, it could result in very different concentrations of active clotting factor. CONCLUSIONS As demonstrated, around 40% of patients if switched from FL-rFVIII to BDD-rFVIII would have lower concentrations of FVIII in the blood. It is essential that clinicians are aware of this possibility and that there is sufficient and appropriate follow-up of patients with hemophilia A who are switching the type of factor concentrate used in their treatment.