Apolipoprotein D (apoD) is expressed in the brain and levels are increased in affected brain regions in Alzheimer's disease (AD). The role that apoD may play in regulating AD pathology has not been addressed. Here, we crossed both apoD-null mice and Thy-1 human apoD transgenic mice with APP-PS1 amyloidogenic AD mice. Loss of apoD resulted in a nearly 2-fold increase in hippocampal amyloid plaque load, as assessed by immunohistochemical staining. Conversely, transgenic expression of neuronal apoD reduced hippocampal plaque load by approximately 35%. This latter finding was associated with a 60% decrease in amyloid β 1-40 peptide levels, and a 34% decrease in insoluble amyloid β 1-42 peptide. Assessment of β-site amyloid precursor protein cleaving enzyme-1 (BACE1) levels and proteolytic products of amyloid precursor protein and neuregulin-1 point toward a possible association of altered BACE1 activity in association with altered apoD levels. In conclusion, the current studies provide clear evidence that apoD regulates amyloid plaque pathology in a mouse model of AD.