The signal regulatory protein-β1 (SIRPβ1) is a DAP12-associated transmembrane receptor expressed in a subset of hematopoietic cells. Recently, it was shown that peritoneal macrophages express SIRPβ1, which positively regulated phagocytosis. Here, we found that SIRPβ1 was up-regulated and acted as a phagocytic receptor on microglia in amyloid precursor protein J20 (APP/J20) transgenic mice and in Alzheimer’s disease (AD) patients. Interferon (IFN)-γ and IFN-β stimulated gene transcription of SIRPβ1 in cultured microglia. Activation of SIRPβ1 on cultured microglia by cross-linking antibodies induced reorganization of the cytoskeleton protein β-actin and suppressed lipopolysaccharide-induced gene transcription of tumor necrosis factor-α and nitric oxide synthase-2. Furthermore, activation of SIRPβ1 increased phagocytosis of microsphere beads, neural debris, and fibrillary amyloid-β (Aβ). Phagocytosis of neural cell debris and Aβ was impaired after lentiviral knockdown of SIRPβ1 in primary microglial cells. Thus, SIRPβ1 is a novel IFN-induced microglial receptor that supports clearance of neural debris and Aβ aggregates by stimulating phagocytosis.