Factor V Arg506Gln is the most common genetic risk factor for venous thrombosis and is associated with myocardial infarction in young women, especially among smokers. The authors studied the relation of factor V Arg506Gln to cardiovascular mortality in older women in a prospective cohort study of 12,239 women, living in the city of Utrecht, who were initially aged between 52 and 67 years. Women were followed on vital status between 1976 and 1995 (168,513 years). The factor V Arg506Gln mutation was determined in urine samples of 524 women who died of cardiovascular disease and in a reference group of 517 women who did not. Data were analyzed using a nested case-referent analysis. Factor V Arg506Gln heterozygosity was not associated with the risk of mortality by myocardial infarction, cerebrovascular disease, and other cardiovascular disease, with respective rate ratios and 95% confidence intervals being 1.1 (0.5-2.3), 1.2 (0.5-3.1), and 0.6 (0.2-1.7). No evidence of association was found in subgroups of smokers and age. Factor V Arg506Gln is not a risk factor for cardiovascular mortality in older women. Discrepancies with other studies may be explained by different study populations, as age and sex may modify both the frequency of cardiovascular disease and the effect of its risk factors.