Background: von Willebrand factor (VWF) is a large multimeric plasma glycoprotein. It plays an important role in haemostasis by promoting platelet adhesion and aggregation at sites of blood vessel damage and by binding to and prolonging the half-life of coagulation factor VIII (FVIII). VWF is synthesised in endothelial cells where it undergoes post-translational modifications including glycosylation and multimerisation. VWF levels vary considerably in the normal population and several factors have been associated with this variation including ABO blood group and age. However, known factors only account for ~65% of variation in level. Previous studies suggest that other genetic loci, including VWF, FUT3 and CLEC4M also influence VWF level. Aims: To identify genetic factors that influence VWF plasma level in the normal population and to investigate the mechanisms by which these genetic factors influence VWF level. Methods: DNA samples and phenotypic data (including VWF levels, age, gender and ABO blood group) were available for ~1100 healthy individuals (HC). Analysis was conducted on VWF, FUT3, FUT5, FUT6 and CLEC4M. In silico analysis was used to identify variants predicted to affect expression or activity. Variants of interest were then genotyped in HC and their association with VWF level was investigated. In vitro studies were used to investigate the effect of these variants on VWF protein and mRNA expression, exon splice enhancer (ESE) motifs, splicing and mRNA half-life. Results: Investigation of 111 single nucleotide variants (SNV) in VWF identified 11 with significant association with VWF plasma level, of which c.2385T > C and c.2365A > G had been reported in previous studies. In vitro analysis showed that both were associated with increased protein, mRNA level and mRNA half-life. Investigation of variants in FUT3, FUT5 and FUT6 showed that only FUT3 c.202T > C was significantly associated with VWF plasma level. Investigation of CLEC4M confirmed the association of a 23 amino acid variable number of tandem repeats (VNTR) with VWF plasma level. Conclusion: Variants within and outside VWF are found to be significantly associated with VWF plasma level through interfering with protein or mRNA levels. These factors were shown to have an additive effect and can be considered as risk factors for bleeding or cardiovascular disease.