Presence of the ε4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), although the mechanism(s) by which it confers this risk is unknown. ApoE may play a direct role in AD neuropathology by modulating neuronal structure. We previously showed that apoE3-containing β- very low density lipoprotein (β-VLDL) can stimulate neurite outgrowth to a significantly greater extent than apoE4-enriched β-VLDL in a central nervous system-derived neuronal cell line and that this effect is mediated by interaction with the low density lipoprotein receptor-related protein (LRP). To determine whether similar differences exist when apoE is associated with other lipoprotein particles, the effects of high density lipoprotein (HDL) derived from plasma and cerebrospinal fluid were defined. ApoE3-enriched HDL significantly enhanced neurite outgrowth as compared with apoE4-enriched HDL, and the majority of this stimulation was blocked in the presence of the receptor-associated protein or a neutralizing antibody to LRP. We also found that cholesterol esterification in the presence of apoE-containing plasma HDL was attenuated in fibroblasts lacking LRP. Therefore, apoE-containing HDL can serve as an LRP ligand, and apoE isoform-specific effects on neurite outgrowth are observed when HDL is the carrier particle.