Experimental autoimmune encephalomyelitis (EAE) is a CD4⁺ T lymphocyte–mediated disease of the central nervous system (CNS) characterized by mononuclear cell infiltration, demyelination, and paralysis. We previously demonstrated a role for chemokines in acute and relapsing EAE pathogenesis. Presently, we investigated the role of CC chemokine receptor 2 (CCR2) in acute EAE. CCR2^−/− mice did not develop clinical EAE or CNS histopathology, and showed a significant reduction in T cell– and CNS-infiltrating CD45^highF4/80⁺ monocyte subpopulations. Peripheral lymphocytes from CCR2^−/− mice produced comparable levels of interferon-gamma (IFN-γ) and interleukin (IL)-2 in response to antigen-specific restimulation when compared with control mice. Adoptively transferred myelin oligodendrocyte glycoprotein 35-55–specific T cells lacking expression of CCR2 were able to induce EAE, whereas CCR2^−/− recipients of wild-type T cells failed to develop disease. These results suggest that CCR2 expression on host-derived mononuclear cells is critical for disease induction.