For vaccine development, it is critical to understand the regulatory mechanisms determining resistance and immunopathology against mycoplasma respiratory diseases. The present study evaluated the contribution of the polarizing cytokines interferon γ (IFN-γ) and interleukin 4 (IL-4) in the regulation of mycoplasma-specific immunity. The absence of a single cytokine (either IFN-γ or IL-4) uniquely altered the expression of multiple chemokines and cytokines in the lungs of uninfected mice and influenced responses to mycoplasma infection. Most importantly, prior nasal-pulmonary immunization of IFN-γ-/- mice led to exacerbated mycoplasma disease, whereas immunized IL-4-/- mice were dramatically more resistant than wild-type mice. Helper T cell type 2 responses in IFN-γ-/- mice corresponded to immunopathologic reactions that developed after mycoplasma infection or immunization. Thus, adaptive immunity clearly can independently promote either protection or immunopathology against mycoplasma infection, and optimal vaccination appears to be dependent on promoting protective IFN-γ-dependent networks (perhaps helper T cell type 1 responses) while minimizing the effect of IL-4-mediated responses, which dampen the generation of protective immunity.