BACKGROUND: Apolipoprotein E has been associated with hippocampal volume loss in Alzheimer's disease and in elderly controls. In this study, we examined the role of apolipoprotein E and hippocampal volume change in 45 older nondemented depressed subjects. All had baseline and 2-year magnetic resonance imaging scans. METHODS: Hippocampal volumes were determined using a semiautomated method. RESULTS: Compared with 36 depressed subjects without an apolipoprotein E epsilon4 allele, 9 subjects with at least one APOE epsilon4 allele showed significant decline in hippocampal volume, particularly in the right hippocampus. In a logistic model, percent change in right hippocampal volume remained associated with presence of an APOE epsilon4 allele after controlling for age, gender, Mini-Mental State Examination score, and baseline total cerebral volume. CONCLUSIONS: Future studies are needed to explain this association and to determine whether the finding for the right hippocampus has a biological basis, or if it is merely a function of small sample size.