The authors conducted a follow-up study of 16 patients with late-life depression approximately 6 years after their initial assessment to evaluate the relationships between apolipoprotein-E (APO-E) status and white-matter hyperintensities (WMH). Ten patients had WMH at baseline, and four patients demonstrated an increase in WMH size over time. Three of four patients with the APO-E epsilon 4 allele demonstrated an increase in WMH over time, and only 1 of 12 patients without an epsilon 4 allele had an increase in WMH. Three of four patients with APO-E epsilon 4 allele developed a chronic course of major depression at follow-up. Patients with APO-E epsilon 4 had a higher number of depressive episodes and lower age at onset. APO-E may be a risk factor for cerebrovascular disease associated with late-life depression and may affect the clinical characteristics and disease course of depression.