It has been suggested that IL-17RC forms a complex with IL-17RA to mediate the functions of IL-17A and IL-17F homodimers as well as IL-17A/F heterodimers. It is still unclear whether IL-17RC is absolutely required for the signaling of IL-17 cytokines in vivo. By using Il-17rc-deficient mice, we show that IL-17RC is essential for the signaling of IL-17A, IL-17F, and IL-17A/F both in vitro and in vivo. IL-17RC does not preassociate with IL-17RA on the cell surface; rather IL-17A can induce the formation of an IL-17RC and IL-17RA complex. This process is not dependent on the intracellular similar expression to fibroblast growth factor genes and IL-17Rs (SEFIR) domain of IL-17RC, but the SEFIR is essential in IL-17A signal transduction. Finally, Il-17rc(-/-) mice develop much milder disease in an experimental autoimmune encephalomyelitis model, supporting an essential role for IL-17RC in mediating immune-mediated CNS inflammation.