BACKGROUND AND PURPOSE: Cerebral white matter lesions (WMLs) are frequently found on magnetic resonance imaging scans in both cognitively intact and demented elderly persons. Vascular risk factors, especially hypertension, are related to their presence. However, not every person with vascular risk factors has WMLs, which suggests interaction with other determinants, eg, genetic factors. The epsilon4 allele of the apolipoprotein E gene (apoE) may be a candidate because this allele is associated with both the vascular risk factors and the consequences (cognitive impairment, dementia) of WMLs. METHODS: We investigated apoE genotype, blood pressure levels, and their interaction in relation to subcortical and periventricular WMLs in 971 participants in the Rotterdam Scan Study. RESULTS: ApoE epsilon4 carriers had a significantly higher subcortical WML volume than did apoE epsilon3epsilon3 carriers (adjusted mean difference, 0.5; 95% confidence interval, 0.2 to 0.8), irrespective of hypertension. This was not found for periventricular WMLs. Participants with both hypertension and at least 1 apoE epsilon4 allele had the highest degree of both types of WML; the interaction was statistically significant for subcortical WMLs (P=0.016). CONCLUSIONS: apoE epsilon4 carriers are at increased risk for WMLs if they suffer from hypertension as well. This may reflect a diminished capacity for neuronal repair in apoE epsilon4 carriers.