Context The genetic causes of deep vein thrombosis ( DVT) are not fully understood. Objective To identify single- nucleotide polymorphisms ( SNPs) associated with DVT. Design, Setting, and Patients We used 3 case- control studies of first DVT. A total of 19 682 gene- centric SNPs were genotyped in 443 cases and 453 controls from the Leiden Thrombophilia Study ( LETS, 1988- 1992). Twelve hundred six SNPs associated with DVT were reinvestigated in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study ( MEGA- 1, 1999- 2004) in a subset of 1398 cases and 1757 controls. Nine SNPs associated with DVT in both LETS and MEGA- 1 were investigated a third time in 1314 cases and 2877 controls from MEGA- 2, a second subset of MEGA. Additional SNPs close to one SNP in CYP4V2 were genotyped in LETS and MEGA- 1. Main Outcome Measure Odds ratios ( ORs) for DVT were estimated by logistic regression. False discovery rates served to investigate the effect of multiple hypothesis testing. Results Of 9 SNPs genotyped in MEGA- 2, 3 were strongly associated with DVT ( P <. 05; false discovery rate <=. 10): rs13146272 in CYP4V2 ( risk allele frequency, 0.64), rs2227589 in SERPINC1 ( risk allele frequency, 0.10), and rs1613662 in GP6 ( risk allele frequency, 0.84). The OR for DVT per risk allele was 1.24 ( 95% confidence interval [ 95% CI], 1.11- 1.37) for rs13146272, 1.29 ( 95% CI, 1.10- 1.49) for rs2227589, and 1.15 ( 95% CI, 1.01- 1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs ( in CYP4V2, KLKB1, and F11) that were also associated with both DVT ( highest OR per risk allele, 1.39; 95% CI, 1.11- 1.74) and coagulation factor XI level ( highest increase per risk allele, 8%; 95% CI, 5%- 11%). Conclusions We identified SNPs in several genes that were associated with DVT. We also found SNPs in the region around the SNP in CYP4V2 ( rs13146272) that were associated with both DVT and factor XI levels. These results show that common genetic variation plays an important role in determining thrombotic risk.