Summary. Previous reports on the effect of Secretor and Lewis blood groups on plasma factor VIII–von Willebrand factor (FVIII–VWF) levels have produced conflicting findings. To determine whether either or both loci can influence plasma FVIII–VWF complex levels, we studied the relationship between Secretor and Lewis genotypes, determined definitively using polymerase chain reaction–restriction fragment length polymorphism analysis, and plasma FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) levels in 136 healthy volunteers. Overall, significantly higher VWF:Ag levels were found in those individuals homozygous for the Se allele (genotype SeSe) than in those heterozygous for the Se allele (P < 0·001). To minimize any confounding influence of ABO genotype/phenotype, we investigated the relationship between Secretor genotype and plasma FVIII–VWF levels within individuals of the same ABO blood group genotype. In the subgroup analysis of group O1O1 individuals alone, VWF:Ag levels were again significantly higher in those individuals with Secretor genotype SeSe than in those either heterozygous or homozygous for the se null allele. Among A1O1 subjects, homozygous Secretors also had significantly higher VWF:Ag levels. In contrast, we found no relationship between Lewis genotype and either VWF:Ag or FVIII:C levels. This study is the first based on genotypic rather than serological analysis, and resolves the previously confounding effects of the Lewis and Secretor loci on plasma FVIII–VWF complex levels.