Mice exposed for 20 min daily to aerosolized ovalbumin (OVA) for 10 d at concentrations from 1 to 0.01% OVA made greatly reduced immunoglobulin (Ig)-E responses to subsequent immunogenic OVA challenges, given either intraperitoneally or by aerosol. This IgE-specific unresponsiveness lasted for at least four months. However, these aerosol-treated mice were primed for larger OVA-specific IgG1 and IgG2a responses. The specific reduction in IgE responses was not due to preferential induction of a T helper (Th)-1 response as aerosol OVA– primed mice made greatly reduced Th2 and no detectable Th1 response after rechallenge in vitro. Consistent with this, the increase in circulating eosinophils observed in control Th2-primed mice was absent in aerosol OVA–treated animals. Interferon (IFN)-γ was not required for this unresponsiveness, as IFN-γ knockout mice and anti–IFN-γ antibody-treated wild-type mice had greatly reduced levels of IgE similar to wild-type controls. CD8⁺ T cells played a relatively small role as IgE responses were reduced to about the same extent in β₂ microglobulin-deficient, or in anti-CD8–treated wild-type mice as in normal mice after aerosol OVA treatment. Similarly, T cell receptor (TCR)-γ/δ T cells were not required for maximal inhibition of the IgE response. These results demonstrate that exposure to inhaled protein antigens can induce a state of unresponsiveness of CD4⁺ T cells that results in a prolonged loss of IgE and eosinophil responses to subsequent challenges. This T cell unresponsiveness was shown not to require CD8⁺ or TCR-γ/δ⁺ T cells or IFN-γ.