Abstract Macrophage surface SIRPα, a ITIMs-containing inhibitory signaling receptor, plays a pivotal role in controlling macrophage phagocytosis of host cells, including healthy self-cells, cancerous and apoptotic cells, through interactions with CD47 expressed on target cells. Utilizing SIRPα-/- and CD47-/- mice, we further investigated SIRPα-dependent macrophage phagocytosis and found that, while ligation of macrophage SIRPα by CD47 triggering inhibitory signaling prohibits phagocytosis, depletion of SIRPα does not immediately render/enhance macrophage phagocytosis. In contrast, SIRPα-/- mice, and also CD47-/- mice, display no signs of macrophage-mediated tissue-destruction or anemia. In adoptive transfer experiments, SIRPα-/- mice demonstrated phagocytic suppression and failure of clearance of CD47-/- RBC, while WT mice hastily cleared CD47-/- RBC in the spleen. We found that treating SIRPα-/- macrophages or mice with inflammatory cytokines especially IL-17, but not IFNγ, releases such functional suppression resulting in significantly augmented macrophage phagocytosis (splenomegaly) and anemia in vivo. IL-17 also largely promotes SIRPα-dependent phagocytosis of macrophages derived from WT mice. Remarkably, we observed that IL-17-treated SIRPα-/- macrophages aggressively ingest cancer cells in vitro, and IL-17-adminitrated SIRPα-/- and WT mice completely cleared and largely delayed, respectively, implanted Lewis lung tumors and B16 melanoma in vivo.