In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45^int/CD11b⁺/CD11c⁻ microglia at days 6–7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of “circulating” (Gr1⁻(Ly6C^lo)CX3CR1⁺) and “inflammatory” (Gr1^hi/Ly6C^hi/CCR2⁺) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS–enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP⁺) microglia expressing GR1⁺(Ly6C⁺) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6C^hi/CD115⁺) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP⁺ microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.