Abstract Ischemic heart disease is caused by a combination of and interaction between a number of genetic and environmental factors. In a study of a group of healthy men from the United Kingdom, such an interaction was identified between the levels of plasma triglycerides and genetic variation determining plasma levels of factor VII, a clotting factor that is associated with risk of ischemic heart disease. We previously reported a common genetic polymorphism of the factor VII gene that changes arginine at residue 353 to a glutamine (Arg353 ->Gln) and showed that healthy men who carry the allele for Gln353 had lower plasma levels of factor VII coagulant activity. This association is strongly confirmed in a new sample. Compared with 301 men with the allele for Arg353, 63 men with one or two alleles for Gln353 had levels of factor VII coagulant activity that were 20% lower (97.8% [95% confidence interval (CI), 95.2% to 100.4%] and 78.2% [CI, 73.8% to 82.9%], respectively; p<.0001), with similar genotype-associated differences observed for levels of factor VII antigen. The 6 men who were homozygous for the Gln353 allele had mean levels of factor VII coagulant activity and antigen that were lower by 40% and 50%, respectively. In an assay using bovine thromboplastin, which is specific for the cleaved (activated) form of factor VII, they had levels lower by 60%, suggesting that the major effect of the Gln353 substitution is to reduce the proportion of the circulating zymogen that is activated. Factor VII coagulant activity in this sample was strongly and positively correlated with plasma triglyceride levels (r=.223, p<.0001), but the relation was confined to only those with the allele for Arg353 (r=.325, p<.001) and absent in those carrying the allele for Gln353 (r= .03, not significant); this interaction between genotype and plasma triglycerides was highly significant (P = .007). Because of this interaction, individuals homozygous for the allele for Arg353, whose plasma triglyceride levels were in the highest tertile of the sample (>2.0 mmol/L), had mean plasma levels of factor VII coagulant activity that were 20% higher than those in the lowest tertile (<1.3 mmol/L), whereas the corresponding values for individuals with the allele for Gln353 showed a 5% decrease. In addition, in those with two alleles for Arg353, levels of factor VII coagulant activity increased more rapidly over a 2-year follow-up period compared with those with the Gln3S3 allele (average increase, 22.6% and 13.6%, respectively; p<.03). These differences associated with the Gln353 genotype are likely to be of clinical importance because in middle-aged men, an increase in factor VII coagulant activity of 25% is associated with an 82% increase in the risk of experiencing a fatal ischemic event over 5 years. Carriers of the allele for Gln353, who represent approximately 20% of the general population, have lower plasma levels of factor VII coagulant activity and thus a lower likelihood of experiencing thrombotic ischemic events.