Several endogenous cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are necessary for eliminatingHistoplasma capsulatum from tissues. In this study, we explored the efficacy of recombinant murine GM-CSF in the treatment of pulmonary histoplasmosis. This cytokine significantly reduced fungal burden in a dose-dependent manner. Pretreatment did not consistently produce a better result than treatment started after infection. The biological effectiveness of GM-CSF was not associated with modulation of lung cytokine production or alteration in lung inflammation, but it directly activated a nonadherent lung cell population to exert anti-Histoplasma activity. GM-CSF improved survival of T-cell-depleted mice exposed to H. capsulatum. When combined with a suboptimal amount of amphotericin B, GM-CSF enhanced survival of normal or T-cell-depleted mice given a lethal challenge. These results suggest that this cytokine may be useful as an adjunctive treatment for histoplasmosis.