Multiple endogenous mechanisms exist to inhibit thymic development of functional autoreactive T cells. In spite of this, autoreactive CD4+ T cell populations persist in normal individuals and retain the capacity to initiate autoimmune disease. Thus, additional regulatory mechanisms operative in the peripheral immune system are required to protect against both the generation of self-directed immune responses and the initiation of autoimmune diseases. One such mechanism involves the active inhibition of T cell responses by CD4+CD25+ regulatory T (T(reg)) cells. In this study, we investigated the protective role of T(reg) cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Our findings indicate that T(reg) cells confer significant protection from the development of MOG(35-55)-induced EAE that may result from the promotion of a protective Th2 response and decreased homing of autoreactive cells to the CNS. Importantly, T(reg) cells differentially expressed elevated levels of ICAM1 and P selectin, molecules which may facilitate T-T cell interactions and contribute to the mechanism by which T(reg) cells inhibit CD4+ T cell responses. Collectively, these findings support a role for T(reg) cells as an active regulatory mechanism that may protect individuals from the onset of MS, as well as other autoimmune diseases.