A number of studies have shown that coronary artery disease severity is associated with the ε2/ ε3/ ε4 polymorphism in the coding region of the apolipoprotein E gene. In this study, we investigated whether the severity of the disease was also influenced by a functional polymorphism (-219 G>T) in the promoter of the gene, and if so, whether the effects of the two polymorphisms were independent. A cohort of 1170 patients with angiographically documented coronary artery disease were genotyped for the two polymorphisms. The frequency of the 4 allele of the ε2/ ε3/ ε4 polymorphism increased linearly with increasing number of diseased vessels, so did the -219T allele of the -219 G>T polymorphism. In the sample as a whole, logistic regression analyses indicated that compared with the G/G genotype, the T/T genotype conferred an odds ratio of 1.598 (95% CI=1.161-2.201, P=0.004) in favor of increased disease severity, and the relationship remained significant after adjustment for ε2/ε 3/ ε4 polymorphism genotypes, plasma cholesterol and triglyceride levels, and other risk factors. The effect of the T/T genotype on disease severity was more significant in patients who did not carry the 4 allele (OR=1.510, 95% CI=1.028-2.221) than in 4 allele carriers (OR=1.303, 95% CI=0.619-2.742). There was considerable linkage disequilibrium between the two polymorphisms (=0.9, PT and 2/3/4 polymorphisms, which may affect respectively the quantity and quality of apoE, have independent and possibly additive effects on coronary artery disease severity.