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Myeloid cells within the CNS, including microglia and border-associated macrophages, play a central role in the neuroinflammatory processes associated with MS. Activation of these cells contributes to the local inflammatory response and promotes the recruitment of additional immune cells into the CNS. SLAMF5 is a cell surface receptor that functions as a homophilic adhesion molecule, capable of modulating immune cell activity through both activating and inhibitory signals. In this study, we investigated the expression and function of SLAMF5 in CNS-resident and peripheral myeloid cells using the murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our findings demonstrate that both total and brain-specific SLAMF5 deficiency in myeloid cells leads to decreased expression of activation and costimulatory molecules, including MHC class II (MHCII) and CD80. This downregulation is mediated, at least in part, through the transcription factor BHLHE40 and its regulation of CD52, resulting in delayed onset and reduced progression of the disease. Furthermore, pharmacological blockade of SLAMF5 in the brain halted disease progression and reduced the expression of myeloid activation markers. In human studies, SLAMF5 blockade in peripheral monocytes from MS patients and in induced pluripotent stem cell (iPSC)-derived microglia reduced the expression of HLA-DR, CD80, and CD52. 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