Apolipoprotein E (apoE) has been implicated as a risk factor for Alzheimer’s disease and in the deposition, fibrillogenesis, and clearance of the amyloid β-peptide (Aβ). To examine the in vivo interactions between apoE and Aβ deposition, we examined 12-month-old transgenic (tg) mice expressing human amyloid precursor protein (APP) with the V717F mutation (APP^V717F homozygous) on an APOE null background. Elimination of APOE resulted in a redistribution and alteration in the character of Aβ deposition in homozygous APP^V717F tg mice, with a dramatic reduction in cortical and dentate gyrus deposition, prominent increase in diffuse CA1 and CA3 deposition, and prevention of the formation of thioflavin-S-positive deposits. These alterations in Aβ deposition were not mediated by significant changes in regional APP expression, low-density lipoprotein receptor-related protein expression, or soluble Aβ levels. Thus, apoE in APP^V717F tg mice not only affects the amount and form of Aβ deposition, but also the anatomical distribution of diffuse Aβ deposits. The APP^V717F tg mouse can serve as a model to investigate genetic influences on the vulnerability of specific neuroanatomical regions to Aβ deposition.