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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of extracellular fibrillar beta-amyloid (fAβ) and accumulation of intraneuronal hyperphosphorylated tau. This pathology is accompanied by a robust inflammatory response mediated by the brain’s resident immune cells, microglia, and macrophages derived from peripheral monocytes which invade the AD brain. These cells produce proinflammatory cytokines and reactive oxygen and nitrogen species, but cannot phagocytose and degrade fAβ.Using nuclear receptor (NR) agonists, we demonstrate that it is possible to change the phenotype of microglia and macrophages in an AD environment and shift them to a pro-phagocytic state. NR agonists of LXR, PPARγ, PPARδ, and their obligate heterodimer partner RXR are able to induce expression of phagocytic TAM receptors MerTK and Axl in vitro. Furthermore, cultured cells respond to NR agonists and phagocytose more cargo in response to fAβ and TAM ligands. Additionally, NR agonists rapidly increase MerTK and Axl levels in mouse models of AD, coincident with reduction of fAβ. Microglia and macrophages in AD animals express high levels of MerTK and Axl on CD45+ plaque associated cells, and the levels of MerTK and Axl are increased further in animals treated with NR agonists. Bexarotene treatment also increases MerTK levels on TREM2+ and CD45hi cells as assayed by flow cytometry, lending data to support the hypothesis that MerTK+ plaque-associated cells are peripherally derived. Strikingly, bexarotene treatment of AD model mice reverses fAβ induced phagocytic deficiency, as demonstrated with a slice-phagocytosis assay.We extend our studies to investigate the role of bexarotene on microglial and macrophage phenotype by utilizing a microarray study to investigate which genes are driven by bexarotene administration. Mononuclear phagocytes isolated from bexarotene treated animals display higher levels of proinflammatory and anti-inflammatory genes compared to vehicle treated controls. Interestingly, many genes involved in IL-1 signaling are differently expressed in bexarotene treated mice.Together our data demonstrate that NR agonists are capable of altering microglial phenotype to a more phagocytic state, thus allowing them to phagocytose Aβ and facilitate its clearance. These data may provide a therapeutic strategy for the treatment of AD and other neurodegenerative diseases.