Abstract Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are autoimmune diseases characterized by extensive infiltration of T cells and myeloid cells into the CNS. Treatments for MS are typically either non-specific immunosuppressive drugs or target adaptive immune cells. However, mounting evidence shows that myeloid cells have essential roles in MS/EAE pathology, but few, if any, MS drugs specifically target myeloid cells. A promising strategy for bridging this gap in treatment modalities for MS may be targeting CSF-1R, a receptor tyrosine kinase with important roles in myeloid cells, including survival and differentiation. We found that blocking CSF-1R signaling attenuated EAE and our analysis of the CNS these mice revealed substantially diminished numbers of inflammatory myeloid cells. These data demonstrate that inhibiting CSF-1R signaling is a viable strategy for attenuating myeloid cell responses during autoimmune neuroinflammation. These studies also suggest that targeting CSF-1R signaling may be an effective approach for treating MS.