The APOE4 genotype is a known risk factor for Alzheimer's disease (AD) and is associated with poorer outcomes after neuropathological insults. To understand APOE's function, we have examined microglia, the CNS specific macrophage, in transgenic mice expressing the human APOE3 and APOE4 gene allele. Our data demonstrate that arginine uptake is enhanced in APOE4 microglia compared to APOE3 microglia. The increased arginine uptake in APOE4 Tg microglia is associated with an increased expression of mRNA for cationic amino acid transporter-1 (Cat1), a constuitively expressed member of the arginine selective transport system (the y+ transport system) found in most cells. The macrophage-associated transporter, cationic amino acid transporter 2B (Cat2B) did not demonstrate a change in mRNA expression. This change in microglial arginine transport suggests a potential impact of the APOE4 gene allele on those biochemical pathways such as NO production or cell proliferation to which arginine contributes.