Macrophages and microglia are critical in the acute inflammatory response and act as final effector cells of demyelination during chronic infection with the neutrotropic MHV‐JHM strain of mouse hepatitis virus (MHV‐JHM). Herein, we show that “immature” F4/80⁺Ly‐6C^hi monocytes are the first cells, along with neutrophils, to enter the MHV‐JHM‐infected central nervous system (CNS). As the infection progresses, macrophages in the CNS down‐regulate expression of Ly‐6C and CD62L, consistent with maturation, and a higher frequency express CD11c, a marker for dendritic cells (DCs). Microglia also express CD11c during this phase of the infection. CD11c⁺ macrophages in the infected CNS exhibit variable properties of immature antigen‐presenting cells (APCs), with modestly increased CD40 and MHC expression, and equivalent potent antigen uptake when compared with CD11c^‐ macrophages. Furthermore, CDllc⁺ and F4/80⁺ macrophages and microglia are localized to areas of demyelination, in some instances directly associated with damaged axons. These results suggest that chronic CNS infection results in the appearance of CD11c‐expressing macrophages from the blood that exhibit properties of immature APCs, are closely associated with areas of demyelination, and may act as final effectors of myelin destruction.