Primary infection to Histoplasma capsulatum often results in a self-limited upper respiratory infection in humans; however, in immunocompromised hosts, disseminated infection can occur through reactivation of a previous infection. Since disseminated histoplasmosis has emerged as a difficult clinical entity to treat in individuals infected with HIV, it was of interest to study the mechanisms involved in maintaining an effective memory immune response. It has been previously shown in a murine model of disseminated histoplasmosis that IL-12, IFN-γ, and TNF-α were important factors in mediating primary protection. To study whether these and other factors were involved in maintaining a protective immune response following secondary infection, normal C57BL/6 mice were first infected with a sublethal dose of H. capsulatum (1× 10 5) and then reinfected 3 wk later with a lethal dose of H. capsulatum (6× 10 5). Under these conditions, all mice developed an effective immune response with sterilizing immunity. Moreover, normal C57BL/6 mice treated with neutralizing Abs against either IL-12, TNF-α, or IFN-γ, depleted of neutrophils or treated with aminoguanidine at the time of reinfection, maintained an effective immune response. The ability of animals to survive a secondary infection in the absence of IFN-γ was verified by showing that IFN-γ−/− mice previously immunized with H. capsulatum and treated with amphotericin B at the time of primary infection had prolonged survival following reinfection with a normally lethal dose. It was further shown that enhancement of TNF-α production in IFN-γ−/− mice was the major mechanism by which these mice were effective in controlling secondary infection.