Previous data have shown an inter-individual difference in the thrombin generating capacity in vitro as well as phenotypic bleeding pattern among patients with severe haemophilia A (FVIII:C activity below 1%). The reason for this is not known. In addition, there are no reports on how thrombin generation may correlate between siblings. In this study, we evaluated and compared thrombin generation in vitro using plasma samples in the presence of by-passing agents (FEIBA and NovoSeven) in 21 unrelated brother pairs with and without inhibitors enrolled in the Malmö International Brother Study (MIBS). Mean maximum thrombin formation in patients with a current inhibitor titer was 182.0 +/- 52.8 mmol mL-1 (FEIBA) and 130.7 +/- 54.9 mmol mL-1 (rFVIIa), respectively, and somewhat higher in those without inhibitors, 222.7 +/- 85.5 mmol mL-1 (FEIBA) and 142.8 +/- 53.6 mmol mL-1 (rFVIIa) (P = 0.16 and 0.29). The variance regarding the maximum thrombin production within a family was significantly lower compared with the thrombin production between families (P < 0.001 for both FEIBA and NovoSeven). Our data indicate that genetically determined factors, other than the FVIII:C activity seems to influence the phenotypic variation in thrombin formation in the presence of by-passing agents. The nature of these determinants remains to be identified.