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Colony-stimulating factor-1 receptor (CSF-1R)-related leukoencephalopathy (CRL) is a neurodegenerative disease that triggers early demyelination, leading to an adult-onset dementia. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor that promotes the activation of microglia and phagocytic clearance of apoptotic neurons and myelin debris. We investigated the role of Trem2 in the demyelination observed in the <i>Csf1r</i>^+/− mouse model of CRL. We show that elevation of <i>Trem2</i> expression and callosal demyelination occur in 4–5-month-old <i>Csf1r</i>^+/− mice, prior to the development of symptoms. Absence of <i>Trem2</i> in the <i>Csf1r</i>^+/− mouse attenuated myelin pathology and normalized microglial densities and morphology in the corpus callosum. <i>Trem2</i> absence also prevented axonal degeneration and the loss of cortical layer V neurons observed in <i>Csf1r</i>^+/− mice. Furthermore, the absence of Trem2 prevented the accumulation of myelin-derived lipids in <i>Csf1r</i>^+/− macrophages and reduced the production of TNF-α after myelin engulfment. These data suggest that TREM2 contributes to microglial dyshomeostasis in CRL.