Cholesterol is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid-β protein precursor processing to form amyloid-β peptides, which are a major constituent of cerebral amyloid plaques associated with Alzheimer's disease. 27-Hydroxycholesterol (27OHC) is synthesized from cholesterol via sterol 27-hydroxylase (CYP27A1) in the brain and, unlike cholesterol, can cross into the brain through the blood brain barrier from the circulation. Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid-β peptide generation, however, this has not been investigated in primary human neurons. Here we show that 27OHC significantly reduced amyloid-β peptide detected in cell culture supernatants from primary human neurons. We also show that 27OHC does not affect α-, β- or γ-secretase activity but does upregulate the liver X receptor (LXR) responsive genes ABCA1, ABCG1 and APOE. These data suggest that 27OHC-mediated reduction in extracellular amyloid-β peptide levels is potentially due to its action as an LXR ligand. © 2009 - IOS Press and the authors. All rights reserved.