EGCG is one of the major catechins in green tea. In this study, we investigated the novel regulatory mechanism of EGCG on amelioration of experimental autoimmune encephalomyelitis (EAE). The data showed that EGCG reduced disease severity in EAE by decreasing brain inflammation and demyelination damage, accompanied by decreased encephalitogenic T cell responses and reduced expression of inflammatory cytokines and chemokines. The effect of EGCG was attributable to its selective inhibition of interferon-gamma and interleukin-17 production in CD4+ T cells, mediated via alteration of the STAT pathway and the transcription factors T-bet and retinoid-related orphan receptor (ROR) gammat/ROR alpha. More important, EGCG has been found novel properties of directly inhibiting Th1 and Th17 cell differentiation in this study. On the other hand, EGCG-treated antigen presenting cells (APC) exhibited reduced co-stimulatory function as a result of altered expression of CD80 and CD86. The results of this study indicate that EGCG is a novel anti-inflammatory agent that could act as a useful drug for the treatment of multiple sclerosis and other neuroinflammatory diseases in the further.