Elimination of apoptotic neurons without inflammation is crucial for brain tissue homeostasis, but the molecular mechanism has not been firmly established. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified innate immune receptor. Here, we show expression of TREM2 in microglia. TREM2 stimulation induced DAP12 phosphorylation, extracellular signal–regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis. Knockdown of TREM2 in microglia inhibited phagocytosis of apoptotic neurons and increased gene transcription of tumor necrosis factor α and nitric oxide synthase-2, whereas overexpression of TREM2 increased phagocytosis and decreased microglial proinflammatory responses. Thus, TREM2 deficiency results in impaired clearance of apoptotic neurons and inflammation that might be responsible for the brain degeneration observed in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy/Nasu-Hakola disease.