Interferon (IFN)-γ reduces airway responses after allergen challenge in mice. The mechanisms of this effect are not clear. These studies investigate whether IFN-γ can reverse prolonged airway responses after allergen challenge in IFN-γ–deficient (IFN-γKO) mice. Sensitized mice (IFN-γKO and wild-type [WT]) were challenged with ovalbumin. Airway responsiveness, eosinophils in bronchoalveolar lavage fluid, and lung lymphocyte subsets (CD4⁺ and CD8⁺) were measured 24 hours and 8 weeks after challenge. In further experiments, we treated IFN-γKO mice with recombinant IFN-γ starting 4 weeks after the challenge for 1 week or 4 weeks. Airway responsiveness, bronchoalveolar lavage eosinophils, and lung CD4⁺ cells were increased 8 weeks after challenge in IFN-γKO but not WT mice. IFN-γ treatment returned lung CD4⁺ cell numbers to values obtained in unchallenged mice. One week of IFN-γ treatment also returned airway responsiveness to baseline levels; however, 4-week treatment with IFN-γ failed to decrease airway responsiveness below levels observed in untreated animals. This suggests that IFN-γ plays an essential role in reversing allergen-induced airway inflammation and hyperresponsiveness and that it may have dual actions on the latter. Observations that IFN-γ reverses airway responses, even when administered after challenge, suggests that IFN-γ treatment could control allergic disease, including asthma.