Background and Purpose— The relationship between white matter lesions (WMLs) and the apolipoprotein E genotype has been controversial from cross-sectional studies and no longitudinal finding has been reported. We investigated whether the apolipoprotein E genotype influences baseline and evolution over 4-year follow-up of WML volumes in a population-based sample of 1779 nondemented subjects aged 65 to 80 years old at enrollment. Methods— The sample consisted of 3C-Dijon study participants who had 2 cerebral MRIs, at entry and at 4-year follow-up. WML volumes were estimated using a fully automatic procedure. We performed analysis of covariance to evaluate the relationship between apolipoprotein E genotype and WML load and progression. Results— Multivariable analyses showed that ε4ε4 individuals had both significantly higher WML volume at baseline and higher WML increase over 4-year follow-up than noncarriers and heterozygous of the ε4 allele for apolipoprotein E genotype. Conclusion— These findings suggest it might be important to take into account WML severity when assessing the relationship between apolipoprotein E and dementia.