The induction phase of experimental autoimmune encephalomyelitis (EAE) in mice is T cell dependent and co-receptors that regulate T cell activation modulate disease development. We report here that mice lacking CD5, an important modulator of T cell activation, exhibit significantly delayed onset and decreased severity of EAE. The resistance to EAE in CD5-/- mice was not due to the inability of T cells to respond efficiently to stimulation with MOG35-55 but was associated with the presence of elevated frequency of apoptotic activated T cells in spleens and DLN. We also observed a net decrease in peripheral activated CD4+ T cells in CD5-/- spleens and DLN 10 days after immunization. We further show that in vivo blockade of CD5 engagement after induction of EAE by soluble CD5-Fc, a treatment that induces elimination of activated T cells, promoted recovery from EAE. Our studies indicate that CD5 regulates survival of activated T cells and provides a target for treatment of T cell-dependent autoimmune diseases such as multiple sclerosis.