An increased risk of ischemic heart disease has been reported in men with the Lewis blood group phenotype Le(a-b-). We have investigated the relationship between Lewis phenotype and cardiovascular risk factors in 1714 participants in the Coronary Artery Risk Development in Young Adults Study, an ongoing investigation on life-styles and evolution of cardiovascular risk factors. No significant differences were observed among Lewis phenotypes for body mass index, blood lipid levels, blood pressure, or clotting factors VII and fibrinogen. However, in white men with blood groups A, B, or AB, and the Le(a-b-) phenotype, significantly higher levels of factor VIII (p < 0.01) and von Willebrand factor (p < 0.03) were observed than in those with other Lewis phenotypes (Le[a+b-] or Le[a-b+]). Two-way analysis of variance indicated a significant interaction between blood group and Lewis phenotype (p = 0.0053) in terms of relationship to factor VIII. A similar trend was observed in black men with blood type A, B, or AB, and phenotype Le(a-b-) for factor VII/von Willebrand factor and in women with blood type A, B, or AB, and phenotype Le(a-b-) for factor VIII. Our data suggest that the Le(a-b-) phenotype and blood groups A, B, and AB, by virtue of their association with raised levels of factor VIII and von Willebrand factor, may be risk markers for future atherothrombotic disease.