Depression with mild cognitive impairment (MCI) may be associated with a high risk of dementia. Likewise, anemia and subcortical ischemic changes might be associated with depression in the elderly individuals. We examined the relationship between anemia, subcortical ischemic changes, and depressive symptoms in 388 elderly patients with MCI (74.0% women, mean age = 71.8) who were evaluated at the Clinical Research Center for Dementia of South Korea. Blood samples were drawn from all consenting participants and depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). We also evaluated the severity of white matter hyperintensities (WMH) on brain using magnetic resonance imaging (MRI). After a multivariable adjustment, we found no significant differences in GDS-15 score between anemic and nonanemic groups (F = 3.0, P = .085) and among WMH level groups (F = 0.6, P = .574) independently. However, the interaction between anemia and the severity of WMH was significantly associated with depressive symptoms (analysis of covariance, F = 7.8, P < .001). In post hoc tests, a higher depressive symptom score was observed in anemic participants with severe WMH. Anemia with severe subcortical ischemic changes appears to be related to depressive symptoms in patients with MCI.