Introduction Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-γ and IL-4 have been shown to suppress Th17 development in vitro, but their potential immunoregulatory roles in vivo are uncertain. The goals of this study were to determine the relationship between Th17 responses and disease severity in CIA and to assess regulation of IL-17 by endogenous IFN-γ and IL-4. Methods DBA1/LacJ mice were immunized with type II collagen in complete Freund's adjuvant (CFA) to induce arthritis, and treated with neutralizing antibody to IFN-γ and/or IL-4. Systemic IL-17, IFN-γ, and IL-4 were measured in serum. At the peak of disease, cytokine production was measured by ELISA of supernatants from spleen, lymph node and paw cultures. Paws were also scored for histologic severity of arthritis. Results Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-γ. Neutralization of IFN-γ accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-γ/IL-4/IL-17 responses in the lymphoid organ were distinct from such responses in the joints. Neutralization of IL-4 led to increased arthritis only in the absence of IFN-γ and was associated with increased bone and cartilage damage without an increase in the levels of IL-17. Conclusions IL-4 and IFN-γ both play protective roles in CIA, but through different mechanisms. Our data suggests that the absolute level of IL-17 is not the only determinant of joint inflammation. Instead, the balance of Th1, Th2 and Th17 cytokines control the immune events leading to joint inflammation.