CTRP4, a secreted protein, plays an important role in protecting against sepsis and energy metabolism; however, its physiological functions in autoimmune disease remain unknown. In this study, we demonstrate that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4 −/− mice because of increased Th17 cell inltration. In vitro, Ctrp4 deciency enhanced the ability of naïve CD4 + T cells to differentiate into Th17 cells. Mechanistically, CTRP4 interfered with the binding of IL-6 to its receptor IL-6R by directly binding to IL-6R and suppressed the activation of STAT3-related pathways in response to IL-6. Furthermore, treatment of induced EAE mice with recombinant CTRP4 protein ameliorated the symptom. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor signaling pathway, may be a potential therapeutic intervention for multiple sclerosis.