This study investigates the role of interferon-gamma (IFN-γ) in protective immunity against Mycobacterium tuberculosis in mice. Mice with a disrupted IFN-γ gene (GKO mice) were unable to control a normally sublethal dose of M. tuberculosis, leading to widespread tissue destruction and necrosis. Despite this, some delayed-type hypersensitivity (DTH)-like reactivity was observed, indicating that IFN-γ is not essential for DTH but is crucial for protective immunity. The study shows that GKO mice, which lack functional IFN-γ, develop a fatal, disseminated form of tuberculosis when infected with M. tuberculosis. This highlights the essential role of IFN-γ in controlling tuberculosis infection. Histological analysis revealed extensive caseous necrosis in major organs, with no evidence of a mononuclear cell response, suggesting that the absence of IFN-γ impairs the activation of macrophages and monocytes necessary for controlling the infection. The study also demonstrates that while TNF may contribute to granuloma formation, IFN-γ is essential for maintaining granuloma integrity and bactericidal mechanisms. Although GKO mice showed some DTH-like responses, the loss of IFN-γ significantly impaired protective immunity against M. tuberculosis. These findings suggest a dissociation between protective immunity and DTH, with other cytokines like TNF, migrating inhibitory factor, and IL-8 potentially playing a role in DTH. The GKO mouse model provides a valuable tool for studying the role of IFN-γ in immunity to various pathogens and for evaluating therapeutic strategies in immunocompromised hosts. This model may be useful in assessing new treatments for tuberculosis and other intracellular infections.This study investigates the role of interferon-gamma (IFN-γ) in protective immunity against Mycobacterium tuberculosis in mice. Mice with a disrupted IFN-γ gene (GKO mice) were unable to control a normally sublethal dose of M. tuberculosis, leading to widespread tissue destruction and necrosis. Despite this, some delayed-type hypersensitivity (DTH)-like reactivity was observed, indicating that IFN-γ is not essential for DTH but is crucial for protective immunity. The study shows that GKO mice, which lack functional IFN-γ, develop a fatal, disseminated form of tuberculosis when infected with M. tuberculosis. This highlights the essential role of IFN-γ in controlling tuberculosis infection. Histological analysis revealed extensive caseous necrosis in major organs, with no evidence of a mononuclear cell response, suggesting that the absence of IFN-γ impairs the activation of macrophages and monocytes necessary for controlling the infection. The study also demonstrates that while TNF may contribute to granuloma formation, IFN-γ is essential for maintaining granuloma integrity and bactericidal mechanisms. Although GKO mice showed some DTH-like responses, the loss of IFN-γ significantly impaired protective immunity against M. tuberculosis. These findings suggest a dissociation between protective immunity and DTH, with other cytokines like TNF, migrating inhibitory factor, and IL-8 potentially playing a role in DTH. The GKO mouse model provides a valuable tool for studying the role of IFN-γ in immunity to various pathogens and for evaluating therapeutic strategies in immunocompromised hosts. This model may be useful in assessing new treatments for tuberculosis and other intracellular infections.