The apolipoprotein E (APOE) epsilon4 allele is associated with elevated cholesterol and risk of atherosclerosis. However, its role in ischemic stroke (IS) remains controversial. We investigated a possible link between IS or the severity of intracranial atherosclerosis and the APOE promoter polymorphisms -219G/T and +113G/C, involved in regulating APOE transcription. We genotyped subjects from a multicentric Belgian case-control study, including 237 middle-aged patients with IS due to small- or large-vessel atherosclerotic stroke and 326 ethnicity- and gender-matched controls and a Finnish autopsy series of 1004 non-stroke cases, who had received a quantitative score of atherosclerosis in the circle of Willis. The APOE epsilon4+ genotype did not associate with IS, but was related to more severe intracranial atherosclerosis score in men (5.4 vs 4.6, P=0.044). Within the most common APOE epsilon3/epsilon3 genotype group, the risk of IS associated with the G-allele of the tightly linked -219G/T (OR=6.2; 95% CI: 1.6-24.3, P=0.009) and +113G/C (OR=7.1; 95% CI: 1.7-29.9, P=0.007) promoter polymorphisms. There was no difference in the severity of intracranial atherosclerosis between -219G/G genotype carriers and non-carriers. This study suggests a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE epsilon4+ genotype did not predict the risk of IS but was associated with severity of subclinical intracranial atherosclerosis in men on the autopsy study. In contrast, the promoter variants were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS.