In the present study, we evaluated the role of CCR2 in a model of viral-induced neurologic disease. An orchestrated expression of chemokines, including the CCR2 ligands monocyte chemoattractant protein-1/CCL2 and monocyte chemoattractant protein-3/CCL7, occurs within the CNS following infection with mouse hepatitis virus (MHV). Infection of mice lacking CCR2 (CCR2−/−) with MHV resulted in increased mortality and enhanced viral recovery from the brain that correlated with reduced (p≤ 0.04) T cell and macrophage/microglial (determined by F4/80 Ag expression, p≤ 0.004) infiltration into the CNS. Moreover, MHV-infected CCR2−/− mice displayed a significant decrease in Th1-associated factors IFN-γ (p≤ 0.001) and RANTES/CCL5 (p≤ 0.002) within the CNS as compared with CCR2+/+ mice. Further, peripheral CD4+ and CD8+ T cells from immunized CCR2−/− mice displayed a marked reduction in IFN-γ production in response to viral Ag and did not migrate into the CNS of MHV-infected recombination-activating gene (RAG) 1−/− mice following adoptive transfer. In addition, macrophage/microglial infiltration into the CNS of RAG1−/− mice receiving CCR2−/− splenocytes was reduced (p≤ 0.05), which correlated with a reduction in the severity of demyelination (p≤ 0.001) as compared with RAG1−/− mice receiving splenocytes from CCR2+/+ mice. Collectively, these results indicate an important role for CCR2 in host defense and disease by regulating leukocyte activation and trafficking.