OBJECTIVE We assessed whether the apolipoprotein ϵ4 (APOE4) genotype affects the relationship of variability in long-term glycemic control (measured by HbA1c SD of multiple measurements) with white matter hyperintensities (WMHs) in elderly patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS WMH volume was generated from structural T1 and fluid-attenuated inversion recovery MRI in each subject. The analysis included 124 subjects; 27 (21.8%) had one or more APOE4 alleles. RESULTS HbA1c variability was associated with significantly higher WMH in APOE4 carriers (r 5 0.47, P 5 0.03), controlling for age, sex, mean HbA1c , number of follow-up years, and a composite of cardiovascular risk factors, but not in noncarriers (r 5 20.04, P 5 0.71; P for interaction 5 0.050). CONCLUSIONS The results suggest that the APOE4 genotype affects the relationship of long-term glycemic control with WMH load so that APOE4 carriers may be more vulnerable to the insults of poor control.