BACKGROUND A fraction of coagulation factor VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). OBJECTIVE Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke, and mortality. PATIENTS/METHODS We measured FVIIa and FVIIa-AT in 3,486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n=2,410) and examined associations of FVII phenotypes with incident cardiovascular disease. RESULTS In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa: β= -25.9 mU/mL per minor allele; FVIIa-AT: β= -26.6 pM per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa: β= 7.8 mU/mL per minor allele; FVIIa-AT: β= 9.9 per minor allele). Adjusted for risk factors, a 1-standard deviation higher FVIIa was associated with increased ischemic stroke risk (hazard ratio (HR) = 1.12; 95% confidence interval (CI): 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all-causes (HR: 1.08, 95% CI: 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR=0.69, 95% CI: 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. CONCLUSIONS Results support the importance of the F7 and PROCR loci on variation in circulating FVIIa and FVIIa-AT. Findings suggest FVIIa is a risk factor for ischemic stroke in older adults while higher FVIIa-AT may reflect mortality risk. This article is protected by copyright. All rights reserved.