Leishmania major, which causes cutaneous leishmaniasis in humans, can also infect mice, in which can cause either a local cutaneous lesion or a fatal disseminated infection. We have previously shown that BALB/c mice injected with antigen-pulsed macrophages derived from bone marrow with granulocyte-macrophage colony-stimulating factor (GMMphi), but not other types of macrophages, were protected from an otherwise lethal infection with L. major The protection induced by GMMphi was shown to be antigen specific and correlated with the induction of a Th1-like response characterized by production of high levels of IFN-gamma, delayed-type hypersensitivity reactivity and long-lived resistance to reinfection. In this report, we show that the protection induced in this disease model correlates with the sustained production of IL-12 synthesis by GMMphi in vitro and in vivo. Moreover, GMMphi deficient in the production of IL-12 were unable to induce protection in this model. Our data, therefore, suggest that a defect in macrophage activation or differentiation may play a significant role in the inability of BALB/c mice to respond effectively to L. major, and this mechanism may also be important in determining resistance to other intracellular parasites.