Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 x 10(-7). Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE.