Interferon-β (IFN-β) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-β was effective in reducing EAE symptoms induced by T helper type 1 (T_H1) cells but exacerbated disease induced by T_H17 cells. Effective treatment in T_H1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In T_H17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-β treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-γ. In the absence of IFN-γ signaling, IFN-β therapy was ineffective in EAE. In RRMS patients, IFN-β nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-β is proinflammatory in T_H17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-β.