Chemokines induce the directional migration of targeted populations of leukocytes during periods of inflammation. Moreover, these molecules also regulate T-cell activation and differentiation following antigenic stimulation. In the present study, the contributions of the CC chemokine ligand 3 (CCL3) to the differentiation and migration of effector T cells in response to viral infection of the central nervous system (CNS) were analyzed. CCL3^−/− mice infected with mouse hepatitis virus exhibited a significant reduction of virus-specific CD8⁺ T cells within the CNS, correlating with delayed viral clearance. Decreased infiltration of CD8⁺ T cells into infected CCL3^−/− mice was associated with enhanced accumulation of primed CD8⁺ T cells in cervical lymph nodes. Although virus-specific CD8⁺ T cells from CCL3^−/− mice were CD44^high, they remained CD62L^high and CD25^low, retained CCR7 expression, and contained limited transcripts of the proinflammatory chemokine receptors CCR5 and CXCR3 compared with virus-specific CD8⁺ T cells from CCL3^+/+ mice. Furthermore, the absence of CCL3 impaired the cytokine production and cytolytic activity of CD8⁺ T cells. In addition, macrophage accumulation within the CNS was significantly decreased in infected CCL3^−/− mice, correlating with reduced demyelination. These results suggest that CCL3 not only mediates macrophage chemotaxis but also significantly enhances differentiation of primed CD8⁺ T cells into effector cells and their release into circulation, thus potentiating effective migration to the site of infection.